ALBERT

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Laura Palzer, Jessica J. Bader, Frances Angel, Megan Witzel, Sydney Blaser, Alexis McNeil, Miles K. Wandersee, N. Adrian Leu, Christopher J. Lengner, Clara E. Cho, Kevin D. Welch, James B. Kirkland, Ralph G. Meyer, Mirella L. Meyer-Ficca〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉NAD〈sup〉+〈/sup〉 is essential for redox reactions in energy metabolism and necessary for DNA repair and epigenetic modification. Humans require sufficient amounts of dietary niacin (nicotinic acid, nicotinamide, and nicotinamide riboside) for adequate NAD〈sup〉+〈/sup〉 synthesis. In contrast, mice easily generate sufficient NAD〈sup〉+〈/sup〉 solely from tryptophan through the kynurenine pathway. We show that transgenic mice with inducible expression of human alpha-amino-beta-carboxy-muconate-semialdehyde decarboxylase (ACMSD) become niacin dependent similar to humans when ACMSD expression is high. On niacin-free diets, these acquired niacin dependency (ANDY) mice developed reversible, mild-to-severe NAD〈sup〉+〈/sup〉 deficiency, depending on the nutrient composition of the diet. NAD deficiency in mice contributed to behavioral and health changes that are reminiscent of human niacin deficiency. This study shows that ACMSD is a key regulator of mammalian dietary niacin requirements and NAD〈sup〉+〈/sup〉 metabolism and that the ANDY mouse represents a versatile platform for investigating pathologies linked to low NAD〈sup〉+〈/sup〉 levels in aging and neurodegenerative diseases.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315626-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Robert M. Witwicki, Muhammad B. Ekram, Xintao Qiu, Michalina Janiszewska, Shaokun Shu, Mijung Kwon, Anne Trinh, Elizabeth Frias, Nadire Ramadan, Greg Hoffman, Kristine Yu, Yingtian Xie, Gregory McAllister, Rob McDonald, Javad Golji, Michael Schlabach, Antoine deWeck, Nicholas Keen, Ho Man Chan, David Ruddy〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Perturbed epigenomic programs play key roles in tumorigenesis, and chromatin modulators are candidate therapeutic targets in various human cancer types. To define singular and shared dependencies on DNA and histone modifiers and transcription factors in poorly differentiated adult and pediatric cancers, we conducted a targeted shRNA screen across 59 cell lines of 6 cancer types. Here, we describe the TRPS1 transcription factor as a strong breast cancer-specific hit, owing largely to lineage-restricted expression. Knockdown of 〈em〉TRPS1〈/em〉 resulted in perturbed mitosis, apoptosis, and reduced tumor growth. Integrated analysis of TRPS1 transcriptional targets, chromatin binding, and protein interactions revealed that TRPS1 is associated with the NuRD repressor complex. These findings uncover a transcriptional network that is essential for breast cancer cell survival and propagation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315997-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Hui Cheng, Xinping Yang, Han Si, Anthony D. Saleh, Wenming Xiao, Jamie Coupar, Susanne M. Gollin, Robert L. Ferris, Natalia Issaeva, Wendell G. Yarbrough, Mark E. Prince, Thomas E. Carey, Carter Van Waes, Zhong Chen〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Cell lines are important tools for biological and preclinical investigation, and establishing their relationship to genomic alterations in tumors could accelerate functional and therapeutic discoveries. We conducted integrated analyses of genomic and transcriptomic profiles of 15 human papillomavirus (HPV)-negative and 11 HPV-positive head and neck squamous cell carcinoma (HNSCC) lines to compare with 279 tumors from The Cancer Genome Atlas (TCGA). We identified recurrent amplifications on chromosomes 3q22–29, 5p15, 11q13/22, and 8p11 that drive increased expression of more than 100 genes in cell lines and tumors. These alterations, together with loss or mutations of tumor suppressor genes, converge on important signaling pathways, recapitulating the genomic landscape of aggressive HNSCCs. Among these, concurrent 3q26.3 amplification and 〈em〉TP53〈/em〉 mutation in most HPV(–) cell lines reflect tumors with worse survival. Our findings elucidate and validate genomic alterations underpinning numerous discoveries made with HNSCC lines and provide valuable models for future studies.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315705-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Osamu Hashimoto, Masayuki Funaba, Kazunari Sekiyama, Satoru Doi, Daichi Shindo, Ryo Satoh, Hiroshi Itoi, Hiroaki Oiwa, Masahiro Morita, Chisato Suzuki, Makoto Sugiyama, Norio Yamakawa, Hitomi Takada, Shigenobu Matsumura, Kazuo Inoue, Seiichi Oyadomari, Hiromu Sugino, Akira Kurisaki〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Brown adipocyte activation or beige adipocyte emergence in white adipose tissue (WAT) increases energy expenditure, leading to a reduction in body fat mass and improved glucose metabolism. We found that activin E functions as a hepatokine that enhances thermogenesis in response to cold exposure through beige adipocyte emergence in inguinal WAT (ingWAT). Hepatic activin E overexpression activated thermogenesis through Ucp1 upregulation in ingWAT and other adipose tissues including interscapular brown adipose tissue and mesenteric WAT. Hepatic activin E-transgenic mice exhibited improved insulin sensitivity. Inhibin βE gene silencing inhibited cold-induced Ucp1 induction in ingWAT. Furthermore, 〈em〉in vitro〈/em〉 experiments suggested that activin E directly stimulated expression of 〈em〉Ucp1〈/em〉 and 〈em〉Fgf21〈/em〉, which was mediated by transforming growth factor-β or activin type I receptors. We uncovered a function of activin E to stimulate energy expenditure through brown and beige adipocyte activation, suggesting a possible preventive or therapeutic target for obesity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315717-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Qian Xiao, Onur Güntürkün〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Functional brain asymmetries depend both on hemisphere-specific factors and lateralized commissural interactions, but their detailed neural mechanisms are mostly unknown. Because birds are visually lateralized, we tested pigeons monocularly in a color discrimination task while recording from single visuomotor forebrain neuron. All birds learned faster and responded quickly with the right eye and left hemisphere. This asymmetry depended on three factors. First, Go-stimulus onset resulted in a higher left hemispheric proportion of excited relative to inhibited neurons such that, second, left-sided visuomotor neurons could trigger the animal’s response faster. Third, the left hemisphere was able to adjust the timing of individual activity patterns of right hemispheric neurons via asymmetrical commissural interactions, such that the right hemisphere came too late to control the response. These results imply that hemispheric dominance in birds is realized by both lateralized activation of forebrain motor areas and shifts of the contralateral spike time.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315742-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Berit Svendsen, Olav Larsen, Maria Buur Nordskov Gabe, Charlotte Bayer Christiansen, Mette M. Rosenkilde, Daniel J. Drucker, Jens Juul Holst〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The intra-islet theory states that glucagon secretion is suppressed when insulin secretion is stimulated, but glucagon’s role in intra-islet paracrine regulation is controversial. This study investigated intra-islet functions of glucagon in mice. We examined glucagon-induced insulin secretion using isolated perfused pancreata from wild-type, GLP-1 receptor (GLP-1R) knockout, diphtheria toxin-induced proglucagon knockdown, β cell-specific glucagon receptor (Gcgr) knockout, and global Gcgr knockout (〈em〉Gcgr〈/em〉〈sup〉−/−〈/sup〉) mice. We found that glucagon stimulates insulin secretion through both Gcgr and GLP-1R. Moreover, loss of either Gcgr or GLP-1R does not change insulin responses, whereas combined blockage of both receptors significantly reduces insulin secretion. Active GLP-1 is identified in pancreatic perfusate from 〈em〉Gcgr〈/em〉〈sup〉−/−〈/sup〉 but not wild-type mice, suggesting that β cell GLP-1R activation results predominantly from glucagon action. Our results suggest that combined activity of glucagon and GLP-1 receptors is essential for β cell secretory responses, emphasizing a role for paracrine intra-islet glucagon actions to maintain appropriate insulin secretion.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315948-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Yumeng Wang, Xiaoyan Xu, Dejan Maglic, Michael T. Dill, Kamalika Mojumdar, Patrick Kwok-Shing Ng, Kang Jin Jeong, Yiu Huen Tsang, Daniela Moreno, Venkata Hemanjani Bhavana, Xinxin Peng, Zhongqi Ge, Hu Chen, Jun Li, Zhongyuan Chen, Huiwen Zhang, Leng Han, Di Du, Chad J. Creighton, Gordon B. Mills〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471831564X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Bernardo Blanco-Sánchez, Aurélie Clément, Javier Fierro, Sarah Stednitz, Jennifer B. Phillips, Jeremy Wegner, Jennifer M. Panlilio, Judy L. Peirce, Philip Washbourne, Monte Westerfield〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Morphogenesis and mechanoelectrical transduction of the hair cell mechanoreceptor depend on the correct assembly of Usher syndrome (USH) proteins into highly organized macromolecular complexes. Defects in these proteins lead to deafness and vestibular areflexia in USH patients. Mutations in a non-USH protein, glutaredoxin domain-containing cysteine-rich 1 (〈em〉GRXCR1〈/em〉), cause non-syndromic sensorineural deafness. To understand the deglutathionylating enzyme function of GRXCR1 in deafness, we generated two 〈em〉grxcr1〈/em〉 zebrafish mutant alleles. We found that hair bundles are thinner in homozygous 〈em〉grxcr1〈/em〉 mutants, similar to the USH1 mutants 〈em〉ush1c〈/em〉 (Harmonin) and 〈em〉ush1ga〈/em〉 (Sans). 〈em〉In vitro〈/em〉 assays showed that glutathionylation promotes the interaction between Ush1c and Ush1ga and that Grxcr1 regulates mechanoreceptor development by preventing physical interaction between these proteins without affecting the assembly of another USH1 protein complex, the Ush1c-Cadherin23-Myosin7aa tripartite complex. By elucidating the molecular mechanism through which Grxcr1 functions, we also identify a mechanism that dynamically regulates the formation of Usher protein complexes.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315687-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Doycho Karagyozov, Mirna Mihovilovic Skanata, Amanda Lesar, Marc Gershow〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Optical recordings of neural activity in behaving animals can reveal the neural correlates of decision making, but brain motion, which often accompanies behavior, compromises these measurements. Two-photon point-scanning microscopy is especially sensitive to motion artifacts, and two-photon recording of activity has required rigid coupling between the brain and microscope. We developed a two-photon tracking microscope with extremely low-latency (360 μs) feedback implemented in hardware. This microscope can maintain continuous focus on neurons moving with velocities of 3 mm/s and accelerations of 1 m/s〈sup〉2〈/sup〉 both in-plane and axially. We recorded calcium dynamics of motor neurons and inter-neurons in unrestrained freely behaving fruit fly larvae, correlating neural activity with stimulus presentations and behavioral outputs, and we measured light-induced depolarization of a visual interneuron in a moving animal using a genetically encoded voltage indicator. Our technique can be extended to stabilize recordings in a variety of moving substrates.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315766-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Joseph Nacson, John J. Krais, Andrea J. Bernhardy, Emma Clausen, Wanjuan Feng, Yifan Wang, Emmanuelle Nicolas, Kathy Q. Cai, Rossella Tricarico, Xiang Hua, Daniela DiMarcantonio, Esteban Martinez, Dali Zong, Elizabeth A. Handorf, Alfonso Bellacosa, Joseph R. Testa, Andre Nussenzweig, Gaorav P. Gupta, Stephen M. Sykes, Neil Johnson〈/p〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Stephen J. Anderson, Marianne C. Kramer, Sager J. Gosai, Xiang Yu, Lee E. Vandivier, Andrew D.L. Nelson, Zachary D. Anderson, Mark A. Beilstein, Rupert G. Fray, Eric Lyons, Brian D. Gregory〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉N〈sup〉6〈/sup〉-methyladenosine (m〈sup〉6〈/sup〉A) is a dynamic, reversible, covalently modified ribonucleotide that occurs predominantly toward 3′ ends of eukaryotic mRNAs and is essential for their proper function and regulation. In 〈em〉Arabidopsis thaliana〈/em〉, many RNAs contain at least one m〈sup〉6〈/sup〉A site, yet the transcriptome-wide function of m〈sup〉6〈/sup〉A remains mostly unknown. Here, we show that many m〈sup〉6〈/sup〉A-modified mRNAs in 〈em〉Arabidopsis〈/em〉 have reduced abundance in the absence of this mark. The decrease in abundance is due to transcript destabilization caused by cleavage occurring 4 or 5 nt directly upstream of unmodified m〈sup〉6〈/sup〉A sites. Importantly, we also find that, upon agriculturally relevant salt treatment, m〈sup〉6〈/sup〉A is dynamically deposited on and stabilizes transcripts encoding proteins required for salt and osmotic stress response. Overall, our findings reveal that m〈sup〉6〈/sup〉A generally acts as a stabilizing mark through inhibition of site-specific cleavage in plant transcriptomes, and this mechanism is required for proper regulation of the salt-stress-responsive transcriptome.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315961-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Christina Karamboulas, Jeffrey P. Bruce, Andrew J. Hope, Jalna Meens, Shao Hui Huang, Natalie Erdmann, Elzbieta Hyatt, Keira Pereira, David P. Goldstein, Ilan Weinreb, Jie Su, Brian O’Sullivan, Rodger Tiedemann, Fei-Fei Liu, Trevor J. Pugh, Scott V. Bratman, Wei Xu, Laurie Ailles〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Overall survival remains very poor for patients diagnosed as having head and neck squamous cell carcinoma (HNSCC). Identification of additional biomarkers and novel therapeutic strategies are important for improving patient outcomes. Patient-derived xenografts (PDXs), generated by implanting fresh tumor tissue directly from patients into immunodeficient mice, recapitulate many of the features of their corresponding clinical cancers, including histopathological and molecular profiles. Using a large collection of PDX models of HNSCC, we demonstrate that rapid engraftment into immunocompromised mice is highly prognostic and show that genomic deregulation of the G1/S checkpoint pathway correlates with engraftment. Furthermore, 〈em〉CCND1〈/em〉 and 〈em〉CDKN2A〈/em〉 genomic alterations are predictive of response to the CDK4and CDK6 inhibitor abemaciclib. Overall, our study supports the pursuit of CDK4 and CDK6 inhibitors as a therapeutic strategy for a substantial proportion of HNSCC patients and demonstrates the potential of using PDX models to identify targeted therapies that will benefit patients who have the poorest outcomes.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315675-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Paula M. Godoy, Nirav R. Bhakta, Andrea J. Barczak, Hakan Cakmak, Susan Fisher, Tippi C. MacKenzie, Tushar Patel, Richard W. Price, James F. Smith, Prescott G. Woodruff, David J. Erle〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Extracellular microRNAs (miRNAs) and other small RNAs are implicated in cellular communication and may be useful as disease biomarkers. We systematically compared small RNAs in 12 human biofluid types using RNA sequencing (RNA-seq). miRNAs and tRNA-derived RNAs (tDRs) accounted for the majority of mapped reads in all biofluids, but the ratio of miRNA to tDR reads varied from 72 in plasma to 0.004 in bile. miRNA levels were highly correlated across all biofluids, but levels of some miRNAs differed markedly between biofluids. tDR populations differed extensively between biofluids. Y RNA fragments were seen in all biofluids and accounted for 〉10% of reads in blood plasma, serum, and cerebrospinal fluid (CSF). Reads mapping exclusively to Piwi-interacting RNAs (piRNAs) were very rare, except in seminal plasma. These results demonstrate extensive differences in small RNAs between human biofluids and provide a useful resource for investigating extracellular RNA biology and developing biomarkers.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315778-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Jun Yin, Mary Gibbs, Caixia Long, Justin Rosenthal, Hyong S. Kim, Anna Kim, Chengyu Sheng, Peng Ding, Uzma Javed, Quan Yuan〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Activity-dependent modifications strongly influence neural development. However, molecular programs underlying their context and circuit-specific effects are not well understood. To study global transcriptional changes associated with chronic elevation of synaptic activity, we performed cell-type-specific transcriptome profiling of 〈em〉Drosophila〈/em〉 ventral lateral neurons (LNvs) in the developing visual circuit and identified activity-modified transcripts that are enriched in neuron morphogenesis, circadian regulation, and lipid metabolism and trafficking. Using bioinformatics and genetic analyses, we validated activity-induced isoform-specific upregulation of 〈em〉Drosophila〈/em〉 lipophorin receptors LpR1 and LpR2, the homologs of mammalian low-density lipoprotein receptor (LDLR) family proteins. Furthermore, our morphological and physiological studies uncovered critical functions of neuronal lipophorin receptors (LpRs) in maintaining the structural and functional integrities in neurons challenged by chronic elevations of activity. Together, our findings identify LpRs as molecular targets for activity-dependent transcriptional regulation and reveal the functional significance of cell-type-specific regulation of neuronal lipid uptake in experience-dependent plasticity and adaptive responses.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315791-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Peter van Galen, Nathan Mbong, Antonia Kreso, Erwin M. Schoof, Elvin Wagenblast, Stanley W.K. Ng, Gabriela Krivdova, Liqing Jin, Hiromitsu Nakauchi, John E. Dick〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Lifelong maintenance of the blood system requires equilibrium between clearance of damaged hematopoietic stem cells (HSCs) and long-term survival of the HSC pool. Severe perturbations of cellular homeostasis result in rapid HSC loss to maintain clonal purity. However, normal homeostatic processes can also generate lower-level stress; how HSCs survive these conditions remains unknown. Here we show that the integrated stress response (ISR) is uniquely active in HSCs and facilitates their persistence. Activating transcription factor 4 (ATF4) mediates the ISR and is highly expressed in HSCs due to scarcity of the eIF2 translation initiation complex. Amino acid deprivation results in eIF2α phosphorylation-dependent upregulation of ATF4, promoting HSC survival. Primitive acute myeloid leukemia (AML) cells also display eIF2 scarcity and ISR activity marks leukemia stem cells (LSCs) in primary AML samples. These findings identify a link between the ISR and stem cell survival in the normal and leukemic contexts.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315973-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Chang Liu, Na Luo, Chun-Yu Tung, Benjamin J. Perrin, Bo Zhao〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Mutations in human 〈em〉GRXCR2〈/em〉, which encodes a protein of undetermined function, cause hearing loss by unknown mechanisms. We found that mouse GRXCR2 localizes to the base of the stereocilia, which are actin-based mechanosensing organelles in cochlear hair cells that convert sound-induced vibrations into electrical signals. The stereocilia base also contains taperin, another protein of unknown function required for human hearing. We show that taperin and GRXCR2 form a complex and that taperin is diffused throughout the stereocilia length in 〈em〉Grxcr2〈/em〉-deficient hair cells. Stereocilia lacking GRXCR2 are longer than normal and disorganized due to the mislocalization of taperin, which could modulate the actin cytoskeleton in stereocilia. Remarkably, reducing taperin expression levels could rescue the morphological defects of stereocilia and restore the hearing of 〈em〉Grxcr2〈/em〉-deficient mice. Thus, our findings suggest that GRXCR2 is critical for the morphogenesis of stereocilia and auditory perception by restricting taperin to the stereocilia base.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315080-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Paula Saz-Leal, Carlos del Fresno, Paola Brandi, Sarai Martínez-Cano, Otto M. Dungan, John D. Chisholm, William G. Kerr, David Sancho〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉β-Glucan-induced trained immunity in myeloid cells leads to long-term protection against secondary infections. Although previous studies have characterized this phenomenon, strategies to boost trained immunity remain undefined. We found that β-glucan-trained macrophages from mice with a myeloid-specific deletion of the phosphatase SHIP-1 (LysMΔSHIP-1) showed enhanced proinflammatory cytokine production in response to lipopolysaccharide. Following β-glucan training, SHIP-1-deficient macrophages exhibited increased phosphorylation of Akt and mTOR targets, correlating with augmented glycolytic metabolism. Enhanced training in the absence of SHIP-1 relied on histone methylation and acetylation. Trained LysMΔSHIP-1 mice produced increased amounts of proinflammatory cytokines upon rechallenge 〈em〉in vivo〈/em〉 and were better protected against 〈em〉Candida albicans〈/em〉 infection compared with control littermates. Pharmacological inhibition of SHIP-1 enhanced trained immunity against 〈em〉Candida〈/em〉 infection in mouse macrophages and human peripheral blood mononuclear cells. Our data establish proof of concept for improvement of trained immunity and a strategy to achieve it by targeting SHIP-1.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315638-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Nagaraj R. Mahajan, Shreesh P. Mysore〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The ability to select the most salient among competing stimuli is essential for animal behavior and operates no matter which spatial locations stimuli happen to occupy. We provide evidence that the brain employs a combinatorially optimized inhibition strategy for selection across all pairs of stimulus locations. With experiments in a key inhibitory nucleus in the vertebrate midbrain selection network, called isthmi pars magnocellularis (Imc) in owls, we discovered that Imc neurons encode visual space with receptive fields that have multiple excitatory hot spots (“lobes”). Such multilobed encoding is necessitated by scarcity of Imc neurons. Although distributed seemingly randomly, the locations of these lobes are optimized across the high-firing Imc neurons, allowing them to combinatorially solve selection across space. This strategy minimizes metabolic and wiring costs, a principle that also accounts for observed asymmetries between azimuthal and elevational coding. Combinatorially optimized inhibition may be a general neural principle for efficient stimulus selection.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315985-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Huan Zhao, Xueying Tian, Lingjuan He, Yan Li, Wenjuan Pu, Qiaozhen Liu, Juan Tang, Jiaying Wu, Xin Cheng, Yang Liu, Qingtong Zhou, Zhen Tan, Fan Bai, Fei Xu, Nicola Smart, Bin Zhou〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Identification of cellular surface markers that distinguish tumorous from normal vasculature is important for the development of tumor vessel-targeted therapy. Here, we show that Apj, a G protein-coupled receptor, is highly enriched in tumor endothelial cells but absent from most endothelial cells of adult tissues in homeostasis. By genetic targeting using 〈em〉Apj-CreER〈/em〉 and 〈em〉Apj-DTRGFP〈/em〉-〈em〉Luciferase〈/em〉, we demonstrated that hypoxia-VEGF signaling drives expansion of Apj〈sup〉+〈/sup〉 tumor vessels and that targeting of these vessels, genetically and pharmacologically, remarkably inhibits tumor angiogenesis and restricts tumor growth. These 〈em〉in vivo〈/em〉 findings implicate Apj〈sup〉+〈/sup〉 vessels as a key driver of pathological angiogenesis and identify Apj〈sup〉+〈/sup〉 endothelial cells as an important therapeutic target for the anti-angiogenic treatment of tumors.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471831578X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Emily N. Gallichotte, Thomas J. Baric, Usha Nivarthi, Matthew J. Delacruz, Rachel Graham, Douglas G. Widman, Boyd L. Yount, Anna P. Durbin, Stephen S. Whitehead, Aravinda M. de Silva, Ralph S. Baric〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉There are four distinct DENV serotypes, and within DENV4, there are five distinct genotypes. The impact of genotypic diversity is not known, nor is it clear whether infection with one DENV4 genotype results in protective immunity against the other genotypes. To measure the impact of DENV4 genetic diversity, we generated an isogenic panel of viruses containing the envelope protein from the different genotypes. We characterized many properties of these viruses and find that a small number of amino acids changes within the envelope have disproportionate impacts on virus biology. Additionally, we observe large differences in the ability of DENV4 antibodies, immune sera, and vaccine sera to neutralize the panel, suggesting that DENV4 immunity might not be equally protective against all DENV4s. Our results support the monitoring of changing or emerging DENV genotypes and their role in escaping pre-existing neutralizing antibodies in people who have been vaccinated or exposed to natural DENV4 infections.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315699-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Sabine E.J. Tanis, Pascal W.T.C. Jansen, Huiqing Zhou, Simon J. van Heeringen, Michiel Vermeulen, Markus Kretz, Klaas W. Mulder〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Epidermal homeostasis requires balanced progenitor cell proliferation and loss of differentiated cells from the epidermal surface. During this process, cells undergo major changes in their transcriptional programs to accommodate new cellular functions. We found that transcriptional and post-transcriptional mechanisms underlying these changes jointly control genes involved in cell adhesion, a key process in epidermal maintenance. Using siRNA-based perturbation screens, we identified DNA and/or RNA binding regulators of epidermal differentiation. Computational modeling and experimental validation identified functional interactions between the matrin-type 2 zinc-finger protein ZMAT2 and the epigenetic modifiers ING5, SMARCA5, BRD1, UHRF1, BPTF, and SMARCC2. ZMAT2 is an interactor of the pre-spliceosome that is required to keep cells in an undifferentiated, proliferative state. RNA immunoprecipitation and transcriptome-wide RNA splicing analysis showed that ZMAT2 associates with and regulates transcripts involved in cell adhesion in conjunction with ING5. Thus, joint control by splicing regulation, histone, and DNA modification is important to maintain epidermal cells in an undifferentiated state.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315808-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Ryo Uehara, Susana M. Cerritelli, Naushaba Hasin, Kiran Sakhuja, Mariya London, Jaime Iranzo, Hyongi Chon, Alexander Grinberg, Robert J. Crouch〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉RNase H2 has two distinct functions: initiation of the ribonucleotide excision repair (RER) pathway by cleaving ribonucleotides (rNMPs) incorporated during DNA replication and processing the RNA portion of an R-loop formed during transcription. An RNase H2 mutant lacking RER activity but supporting R-loop removal revealed that rNMPs in DNA initiate p53-dependent DNA damage response and early embryonic arrest in mouse. However, an RNase H2 AGS-related mutant with residual RER activity develops to birth. Estimations of the number of rNMPs in DNA in these two mutants define a ribonucleotide threshold above which p53 induces apoptosis. Below the threshold, rNMPs in DNA trigger an innate immune response. Compound heterozygous cells, containing both defective enzymes, retain rNMPs above the threshold, indicative of competition for RER substrates between active and inactive enzymes, suggesting that patients with compound heterozygous mutations in 〈em〉RNASEH2〈/em〉 genes may not reflect the properties of recombinantly expressed proteins.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471831595X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 30 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 5〈/p〉 〈p〉Author(s): Martin Y. Fan, Jun Siong Low, Naoki Tanimine, Kelsey K. Finn, Bhavana Priyadharshini, Sharon K. Germana, Susan M. Kaech, Laurence A. Turka〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Although Foxp3〈sup〉+〈/sup〉 regulatory T cells (Tregs) require interleukin-2 (IL-2) for their development, it has been unclear whether continuing IL-2 signals are needed to maintain lineage stability, survival, and suppressor function in mature Tregs. We generated mice in which CD25, the main ligand-binding subunit of the IL-2 receptor, can be inducibly deleted from Tregs after thymic development. In contrast to Treg development, we find that IL-2 is dispensable for maintaining lineage stability in mature Tregs. Although continuous IL-2 signaling is needed for long-term Treg survival, CD25-deleted Tregs may persist for several weeks 〈em〉in vivo〈/em〉 using IL-7. We also observe defects in glycolytic metabolism and suppressor function following CD25 deletion. Thus, unlike developing Tregs in which the primary role of IL-2 is to initiate Foxp3 expression, mature Tregs require continuous IL-2 signaling to maintain survival and suppressor function, but not to maintain lineage stability.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315651-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Kelly A. Zalocusky, Matthew J. Kan, Zicheng Hu, Patrick Dunn, Elizabeth Thomson, Jeffrey Wiser, Sanchita Bhattacharya, Atul J. Butte〈/p〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Shiwei Chen, Teresa Romeo Luperchio, Xianrong Wong, Europe B. Doan, Aaron T. Byrd, Kingshuk Roy Choudhury, Karen L. Reddy, Michael S. Krangel〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉〈em〉Tcrb〈/em〉 locus V(D)J recombination is regulated by positioning at the nuclear periphery. Here, we used DamID to profile 〈em〉Tcrb〈/em〉 locus interactions with the nuclear lamina at high resolution. We identified a lamina-associated domain (LAD) border composed of several CTCF-binding elements that segregates active non-LAD from inactive LAD regions of the locus. Deletion of the LAD border causes an enhancer-dependent spread of histone H3 lysine 27 acetylation from the active recombination center into recombination center-proximal LAD chromatin. This is associated with a disruption to nuclear lamina association, increased chromatin looping to the recombination center, and increased transcription and recombination of recombination center-proximal gene segments. Our results show that a LAD and LAD border are critical components of 〈em〉Tcrb〈/em〉 locus gene regulation and suggest that LAD borders may generally function to constrain the activity of nearby enhancers.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316413-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Simon R. Scutts, Stuart W. Ember, Hongwei Ren, Chao Ye, Christopher A. Lovejoy, Michela Mazzon, David L. Veyer, Rebecca P. Sumner, Geoffrey L. Smith〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Virus infection is sensed by pattern recognition receptors (PRRs) detecting virus nucleic acids and initiating an innate immune response. DNA-dependent protein kinase (DNA-PK) is a PRR that binds cytosolic DNA and is antagonized by vaccinia virus (VACV) protein C16. Here, VACV protein C4 is also shown to antagonize DNA-PK by binding to Ku and blocking Ku binding to DNA, leading to a reduced production of cytokines and chemokines 〈em〉in vivo〈/em〉 and a diminished recruitment of inflammatory cells. C4 and C16 share redundancy in that a double deletion virus has reduced virulence not seen with single deletion viruses following intradermal infection. However, non-redundant functions exist because both single deletion viruses display attenuated virulence compared to wild-type VACV after intranasal infection. It is notable that VACV expresses two proteins to antagonize DNA-PK, but it is not known to target other DNA sensors, emphasizing the importance of this PRR in the response to infection 〈em〉in vivo〈/em〉.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316103-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Jona Mijalkovic, Jaap van Krugten, Felix Oswald, Seyda Acar, Erwin J.G. Peterman〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Cilia are microtubule-based sensing hubs that rely on intraflagellar transport (IFT) for their development, maintenance, and function. Kinesin-2 motors transport IFT trains, consisting of IFT proteins and cargo, from ciliary base to tip. There, trains turn around and are transported back by IFT dynein. The mechanism of tip turnaround has remained elusive. Here, we employ single-molecule fluorescence microscopy of IFT components in the tips of phasmid cilia of living 〈em〉C. elegans〈/em〉. Analysis of the trajectories reveals that while motor proteins and IFT-A particle component CHE-11 mostly turn around immediately, the IFT-B particle component OSM-6 pauses for several seconds. Our data indicate that IFT trains disassemble into at least IFT-A, IFT-B, IFT-dynein, and OSM-3 complexes at the tip, where OSM-6 is temporarily retained or undergoes modification, prior to train reassembly and retrograde transport. The single-molecule approach used here is a valuable tool to study how directional switches occur in microtubule-based transport processes.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316395-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Julyun Oh, So Jung Lee, Rodney Rothstein, Lorraine S. Symington〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The yeast Mre11-Rad50-Xrs2 (MRX) complex has structural, signaling, and catalytic functions in the response to DNA damage. Xrs2, the eukaryotic-specific component of the complex, is required for nuclear import of Mre11 and Rad50 and to recruit the Tel1 kinase to damage sites. We show that nuclear-localized MR complex (Mre11-NLS) catalyzes homology-dependent repair without Xrs2, but MR cannot activate Tel1, and it fails to tether DSBs, resulting in sensitivity to genotoxins, replisome instability, and increased gross chromosome rearrangements (GCRs). Fusing the Tel1 interaction domain from Xrs2 to Mre11-NLS is sufficient to restore telomere elongation and Tel1 signaling to Xrs2-deficient cells. Furthermore, Tel1 stabilizes Mre11-DNA association, and this stabilization function becomes important for DNA damage resistance in the absence of Xrs2. Enforcing Tel1 recruitment to the nuclear MR complex fully rescues end tethering and stalled replication fork stability, and suppresses GCRs, highlighting important roles for Xrs2 and Tel1 to ensure optimal MR activity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316061-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Benoit Souquet, Ellen Freed, Alessandro Berto, Vedrana Andric, Nicolas Audugé, Bernardo Reina-San-Martin, Elizabeth Lacy, Valérie Doye〈/p〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Ayako Nakamura-Ishizu, Takayoshi Matsumura, Patrick S. Stumpf, Terumasa Umemoto, Hitoshi Takizawa, Yuji Takihara, Aled O'Neil, A'Qilah Banu Bte Abdul Majeed, Ben D. MacArthur, Toshio Suda〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉During acute myelosuppression or thrombocytopenia, bone marrow (BM) hematopoietic cells respond rapidly to replenish peripheral blood platelets. While the cytokine thrombopoietin (Thpo) both regulates platelet production and maintains HSC potential, whether Thpo controls megakaryocyte (Mk)-lineage differentiation of HSCs is unclear. Here, we show that Thpo rapidly upregulates mitochondrial activity in HSCs, an activity accompanied by differentiation to an Mk lineage. Moreover, in unperturbed hematopoiesis, HSCs with high mitochondrial activity exhibit Mk-lineage differentiation 〈em〉in vitro〈/em〉 and myeloid lineage-biased reconstitution 〈em〉in vivo〈/em〉. Furthermore, Thpo skewed HSCs to express the tetraspanin CD9, a pattern correlated with mitochondrial activity. Mitochondria-active HSCs are resistant to apoptosis and oxidative stress upon Thpo stimulation. Thpo-regulated mitochondrial activity associated with mitochondrial translocation of STAT3 phosphorylated at serine 727. Overall, we report an important role for Thpo in regulating rapid Mk-lineage commitment. Thpo-dependent changes in mitochondrial metabolism prime HSCs to undergo direct differentiation to an Mk lineage.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316486-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Ami Patel, Daniel H. Park, Carl W. Davis, Trevor R.F. Smith, Anders Leung, Kevin Tierney, Aubrey Bryan, Edgar Davidson, Xiaoying Yu, Trina Racine, Charles Reed, Marguerite E. Gorman, Megan C. Wise, Sarah T.C. Elliott, Rianne Esquivel, Jian Yan, Jing Chen, Kar Muthumani, Benjamin J. Doranz, Erica Ollmann Saphire〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Synthetically engineered DNA-encoded monoclonal antibodies (DMAbs) are an 〈em〉in vivo〈/em〉 platform for evaluation and delivery of human mAb to control against infectious disease. Here, we engineer DMAbs encoding potent anti-〈em〉Zaire ebolavirus〈/em〉 (EBOV) glycoprotein (GP) mAbs isolated from Ebola virus disease survivors. We demonstrate the development of a human IgG1 DMAb platform for 〈em〉in vivo〈/em〉 EBOV-GP mAb delivery and evaluation in a mouse model. Using this approach, we show that DMAb-11 and DMAb-34 exhibit functional and molecular profiles comparable to recombinant mAb, have a wide window of expression, and provide rapid protection against lethal mouse-adapted EBOV challenge. The DMAb platform represents a simple, rapid, and reproducible approach for evaluating the activity of mAb during clinical development. DMAbs have the potential to be a mAb delivery system, which may be advantageous for protection against highly pathogenic infectious diseases, like EBOV, in resource-limited and other challenging settings.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316516-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Anne Jørgensen, Joni Macdonald, John E. Nielsen, Karen R. Kilcoyne, Signe Perlman, Lene Lundvall, Lea Langhoff Thuesen, Kristine Juul Hare, Hanne Frederiksen, Anna-Maria Andersson, Niels E. Skakkebæk, Anders Juul, Richard M. Sharpe, Ewa Rajpert-De Meyts, Rod T. Mitchell〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Disruption of human fetal testis development is widely accepted to underlie testicular germ cell cancer (TGCC) origin and additional disorders within testicular dysgenesis syndrome (TDS). However, the mechanisms for the development of testicular dysgenesis in humans are unclear. We used 〈em〉ex vivo〈/em〉 culture and xenograft approaches to investigate the importance of Nodal and Activin signaling in human fetal testis development. Inhibition of Nodal, and to some extent Activin, signaling disrupted seminiferous cord formation, abolished AMH expression, reduced androgen secretion, and decreased gonocyte numbers. Subsequent xenografting of testicular tissue rescued the disruptive effects on seminiferous cords and somatic cells but not germ cell effects. Stimulation of Nodal signaling increased the number of germ cells expressing pluripotency factors, and these persisted after xenografting. Our findings suggest a key role for Nodal signaling in the regulation of gonocyte differentiation and early human testis development with implications for the understanding of TGCC and TDS origin.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316681-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Krishna C. Chinta, Md. Aejazur Rahman, Vikram Saini, Joel N. Glasgow, Vineel P. Reddy, Jeremie M. Lever, Shepherd Nhamoyebonde, Alasdair Leslie, Ryan M. Wells, Amie Traylor, Rajhmun Madansein, Gene P. Siegal, Veena B. Antony, Jessy Deshane, Gordon Wells, Kievershen Nargan, James F. George, Pratistadevi K. Ramdial, Anupam Agarwal, Adrie J.C. Steyn〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that controls inflammatory responses and redox homeostasis; however, its role during pulmonary tuberculosis (TB) remains unclear. Using freshly resected human TB lung tissue, we examined the role of HO-1 within the cellular and pathological spectrum of TB. Flow cytometry and histopathological analysis of human TB lung tissues showed that HO-1 is expressed primarily in myeloid cells and that HO-1 levels in these cells were directly proportional to cytoprotection. HO-1 mitigates TB pathophysiology by diminishing myeloid cell-mediated oxidative damage caused by reactive oxygen and/or nitrogen intermediates, which control granulocytic karyorrhexis to generate a zonal HO-1 response. Using whole-body or myeloid-specific HO-1-deficient mice, we demonstrate that HO-1 is required to control myeloid cell infiltration and inflammation to protect against TB progression. Overall, this study reveals that zonation of HO-1 in myeloid cells modulates free-radical-mediated stress, which regulates human TB immunopathology.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316772-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Teresa Lobo-Jarne, Eva Nývltová, Rafael Pérez-Pérez, Alba Timón-Gómez, Thibaut Molinié, Austin Choi, Arnaud Mourier, Flavia Fontanesi, Cristina Ugalde, Antoni Barrientos〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The mitochondrial respiratory chain is organized in a dynamic set of supercomplexes (SCs). The COX7A2L protein is essential for mammalian SC III〈sub〉2〈/sub〉+IV assembly. However, its function in respirasome (SCs I+III〈sub〉2〈/sub〉+IV〈sub〉n〈/sub〉) biogenesis remains controversial. To unambiguously determine the COX7A2L role, we generated 〈em〉COX7A2L〈/em〉-knockout (〈em〉COX7A2L〈/em〉-KO) HEK293T and U87 cells. 〈em〉COX7A2L〈/em〉-KO cells lack SC III〈sub〉2〈/sub〉+IV but have enhanced complex III steady-state levels, activity, and assembly rate, normal 〈em〉de novo〈/em〉 complex IV biogenesis, and delayed respirasome formation. Nonetheless, the KOs have normal respirasome steady-state levels, and only larger structures (SCs I〈sub〉1-2〈/sub〉+III〈sub〉2〈/sub〉+IV〈sub〉2-n〈/sub〉 or megacomplexes) were undetected. Functional substrate-driven competition assays showed normal mitochondrial respiration in 〈em〉COX7A2L〈/em〉-KO cells in standard and nutritional-, environmental-, and oxidative-stress-challenging conditions. We conclude that COX7A2L establishes a regulatory checkpoint for the biogenesis of CIII〈sub〉2〈/sub〉 and specific SCs, but the COX7A2L-dependent MRC remodeling is essential neither to maintain mitochondrial bioenergetics nor to cope with acute cellular stresses.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316474-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Daniel S.J. Miller, Robert D. Bloxham, Ming Jiang, Ilaria Gori, Rebecca E. Saunders, Debipriya Das, Probir Chakravarty, Michael Howell, Caroline S. Hill〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Signal transduction pathways stimulated by secreted growth factors are tightly regulated at multiple levels between the cell surface and the nucleus. The trafficking of cell surface receptors is emerging as a key step for regulating appropriate cellular responses, with perturbations in this process contributing to human diseases, including cancer. For receptors recognizing ligands of the transforming growth factor β (TGF-β) family, little is known about how trafficking is regulated or how this shapes signaling dynamics. Here, using whole genome small interfering RNA (siRNA) screens, we have identified the ESCRT (endosomal sorting complex required for transport) machinery as a crucial determinant of signal duration. Downregulation of ESCRT components increases the outputs of TGF-β signaling and sensitizes cells to low doses of ligand in their microenvironment. This sensitization drives an epithelial-to-mesenchymal transition (EMT) in response to low doses of ligand, and we demonstrate a link between downregulation of the ESCRT machinery and cancer survival.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316450-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Min Guo, Minghai Ge, Michael A. Berberoglu, Jie Zhou, Long Ma, Juan Yang, Qiyan Dong, Yanni Feng, Zhengxing Wu, Zhiqiang Dong〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The mechanisms by which off-response neurons stay quiescent during stimulation are largely unknown. Here, we dissect underlying molecular and circuit mechanisms for the inhibition of off-response ASI neurons during nociceptive Cu〈sup〉2+〈/sup〉 stimulation. ASIs are inhibited in parallel by sensory neurons ASER, ADFs, and ASHs. ASER activates RIC interneurons that release octopamine (OA) to inhibit ASIs through SER-3 and SER-6 receptors. ADFs release 5-HT that acts on the SER-1 receptor to activate RICs and subsequently inhibit ASIs. Furthermore, it is an inherent property of ASIs that only a delayed on response is evoked by Cu〈sup〉2+〈/sup〉 stimulation even when all inhibitory neurons are silenced. Ectopic expression of the ion channel OCR-2, which functions synergistically with OSM-9, in the cilia of ASIs can induce an immediate on response of ASIs upon Cu〈sup〉2+〈/sup〉 stimulation. Our findings elucidate the molecular and circuit mechanisms regulating fundamental properties of ASIs, including their inhibition and delayed response.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316693-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Cody T. Mowery, Jaime M. Reyes, Lucia Cabal-Hierro, Kelly J. Higby, Kristen L. Karlin, Jarey H. Wang, Robert J. Kimmerling, Paloma Cejas, Klothilda Lim, Hubo Li, Takashi Furusawa, Henry W. Long, David Pellman, Bjoern Chapuy, Michael Bustin, Scott R. Manalis, Thomas F. Westbrook, Charles Y. Lin, Andrew A. Lane〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Down syndrome (DS, trisomy 21) is associated with developmental abnormalities and increased leukemia risk. To reconcile chromatin alterations with transcriptome changes, we performed paired exogenous spike-in normalized RNA and chromatin immunoprecipitation sequencing in DS models. Absolute normalization unmasks global amplification of gene expression associated with trisomy 21. Overexpression of the nucleosome binding protein HMGN1 (encoded on chr21q22) recapitulates transcriptional changes seen with triplication of a Down syndrome critical region on distal chromosome 21, and HMGN1 is necessary for B cell phenotypes in DS models. Absolute exogenous-normalized chromatin immunoprecipitation sequencing (ChIP-Rx) also reveals a global increase in histone H3K27 acetylation caused by HMGN1. Transcriptional amplification downstream of HMGN1 is enriched for stage-specific programs of B cells and B cell acute lymphoblastic leukemia, dependent on the developmental cellular context. These data offer a mechanistic explanation for DS transcriptional patterns and suggest that further study of HMGN1 and RNA amplification in diverse DS phenotypes is warranted.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316504-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Natasha Jansz, Tatyana Nesterova, Andrew Keniry, Megan Iminitoff, Peter F. Hickey, Greta Pintacuda, Osamu Masui, Simon Kobelke, Niall Geoghegan, Kelsey A. Breslin, Tracy A. Willson, Kelly Rogers, Graham F. Kay, Archa H. Fox, Haruhiko Koseki, Neil Brockdorff, James M. Murphy, Marnie E. Blewitt〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉We and others have recently reported that the SMC protein Smchd1 is a regulator of chromosome conformation. Smchd1 is critical for the structure of the inactive X chromosome and at autosomal targets such as the 〈em〉Hox〈/em〉 genes. However, it is unknown how Smchd1 is recruited to these sites. Here, we report that Smchd1 localizes to the inactive X via the 〈em〉Xist〈/em〉-HnrnpK-PRC1 (polycomb repressive complex 1) pathway. Contrary to previous reports, Smchd1 does not bind 〈em〉Xist〈/em〉 or other RNA molecules with any specificity. Rather, the localization of Smchd1 to the inactive X is H2AK119ub dependent. Following perturbation of this interaction, Smchd1 is destabilized, which has consequences for gene silencing genome-wide. Our work adds Smchd1 to the PRC1 silencing pathway for X chromosome inactivation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316334-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Kazuhito Gotoh, Takafumi Morisaki, Daiki Setoyama, Katsuhiko Sasaki, Mikako Yagi, Ko Igami, Soichi Mizuguchi, Takeshi Uchiumi, Yoshinori Fukui, Dongchon Kang〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Dendritic cell (DC) maturation induced by Toll-like receptor agonists requires activation of downstream signal transduction and metabolic changes. The endogenous metabolite citrate has recently emerged as a modulator of DC activation. However, the metabolic requirements that support citrate production remain poorly defined. Here, we demonstrate that p32/C1qbp, which functions as a multifunctional chaperone protein in mitochondria, supports mitochondrial metabolism and DC maturation. Metabolic analysis revealed that the citrate increase induced by lipopolysaccharide (LPS) is impaired in p32-deficient DCs. We also found that p32 interacts with dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase [PDH] complex) and positively regulates PDH activity in DCs. Therefore, we suggest that DC maturation is regulated by citrate production via p32-dependent PDH activity. p32-null mice administered a PDH inhibitor show decreased DC maturation and ovalbumin-specific IgG production 〈em〉in vivo〈/em〉, suggesting that p32 may serve as a therapeutic target for DC-related autoimmune diseases.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316462-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Lan Ding, Shuo Wang, Ze-Ting Song, Yupei Jiang, Jia-Jia Han, Sun-Jie Lu, Lin Li, Jian-Xiang Liu〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Plants coordinate their growth and developmental programs with various endogenous signals and environmental challenges. Phytochrome interacting factor 4 (〈em〉PIF4〈/em〉) plays a critical positive role in thermoresponsive gene expression and hypocotyl growth in 〈em〉Arabidopsis〈/em〉, whereas early flowering 3 (ELF3) negatively regulates the activity of PIF4 at elevated temperatures. However, it is unknown how ELF3 activity is regulated at warm temperatures. Here, we report the identification of B-box 18 (BBX18) and BBX23 as important thermomorphogenesis regulators in 〈em〉Arabidopsis〈/em〉. 〈em〉BBX18〈/em〉 and 〈em〉BBX23〈/em〉 mutations result in reduced thermoresponsive hypocotyl elongation. In contrast, 〈em〉BBX18〈/em〉 overexpression promotes hypocotyl growth at elevated temperatures, which depends on either 〈em〉PIF4〈/em〉 or constitutive photomorphogenic 1 (〈em〉COP1〈/em〉). BBX18 and BBX23 interact with ELF3 or COP1. Knocking out 〈em〉BBX18〈/em〉 and 〈em〉BBX23〈/em〉 increases ELF3 abundance under normal and warm temperature conditions. The expression of multiple thermoresponsive genes is impaired in both a 〈em〉PIF4〈/em〉 mutant and a 〈em〉BBX18〈/em〉/〈em〉BBX23〈/em〉 double mutant. Thus, our findings reveal an important role of B-box proteins during thermomorphogenesis and provide insights into our understanding of how warm temperature signals regulate ELF3 activity and 〈em〉PIF4〈/em〉-dependent genes.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316498-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Jinjin Cai, Karla M. Pires, Maroua Ferhat, Bhagirath Chaurasia, Márcio A. Buffolo, Rana Smalling, Ashot Sargsyan, Donald L. Atkinson, Scott A. Summers, Timothy E. Graham, Sihem Boudina〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Autophagy is a homeostatic cellular process involved in the degradation of long-lived or damaged cellular components. The role of autophagy in adipogenesis is well recognized, but its role in mature adipocyte function is largely unknown. We show that the autophagy proteins Atg3 and Atg16L1 are required for proper mitochondrial function in mature adipocytes. In contrast to previous studies, we found that post-developmental ablation of autophagy causes peripheral insulin resistance independently of diet or adiposity. Finally, lack of adipocyte autophagy reveals cross talk between fat and liver, mediated by lipid peroxide-induced Nrf2 signaling. Our data reveal a role for autophagy in preventing lipid peroxide formation and its transfer in insulin-sensitive peripheral tissues.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316292-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Kathleen A. Trychta, Susanne Bäck, Mark J. Henderson, Brandon K. Harvey〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Retention of critical endoplasmic reticulum (ER) luminal proteins needed to carry out diverse functions (e.g., protein synthesis and folding, lipid metabolism) is mediated through a carboxy-terminal ER retention sequence (ERS) and its interaction with KDEL receptors. Here, we demonstrate that depleting ER calcium causes mass departure of ERS-containing proteins from cells by overwhelming KDEL receptors. In addition, we provide evidence that KDELR2 and KDELR3, but not KDELR1, are unfolded protein response (UPR) genes upregulated as an adaptive response to counteract the loss of ERS-containing proteins, suggesting previously unknown isoform-specific functions of the KDEL receptors. Overall, our findings establish that decreases in ER calcium change the composition of the ER luminal proteome and secretome, which can impact cellular functions and cell viability. The redistribution of the ER proteome from inside the cell to the outside has implications for dissecting the complex relationship of ER homeostasis with diverse disease pathologies.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316449-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Vina Tikiyani, Lei Li, Pallavi Sharma, Haowen Liu, Zhitao Hu, Kavita Babu〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The aberrant regulation of Wnt secretion is implicated in various neurological diseases. However, the mechanisms of Wnt release are still largely unknown. Here we describe the role of a 〈em〉C. elegans〈/em〉 tetraspan protein, HIC-1, in maintaining normal Wnt release. We show that HIC-1 is expressed in cholinergic synapses and that mutants in 〈em〉hic-1〈/em〉 show increased levels of the acetylcholine receptor AChR/ACR-16. Our results suggest that HIC-1 maintains normal AChR/ACR-16 levels by regulating normal Wnt release from presynaptic neurons, as 〈em〉hic-1〈/em〉 mutants show an increase in secreted Wnt from cholinergic neurons. We further show that HIC-1 affects Wnt secretion by modulating the actin cytoskeleton through its interaction with the actin-binding protein NAB-1. In summary, we describe a protein, HIC-1, that functions as a neuromodulator by affecting postsynaptic AChR/ACR-16 levels by regulating presynaptic Wnt release from cholinergic motor neurons.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316425-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Jianbo Wu, Nadine Matthias, Jonathan Lo, Jose L. Ortiz-Vitali, Annie W. Shieh, Sidney H. Wang, Radbod Darabi〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Myogenic differentiation of human pluripotent stem cells (hPSCs) has been done by gene overexpression or directed differentiation. However, viral integration, long-term culture, and the presence of unwanted cells are the main obstacles. By using CRISPR/Cas9n, a double-reporter human embryonic stem cell (hESC) line was generated for PAX7/MYF5, allowing prospective readout. This strategy allowed pathway screen to define efficient myogenic induction in hPSCs. Next, surface marker screen allowed identification of CD10 and CD24 for purification of myogenic progenitors and exclusion of non-myogenic cells. CD10 expression was also identified on human satellite cells and skeletal muscle progenitors. 〈em〉In vitro〈/em〉 and 〈em〉in vivo〈/em〉 studies using transgene and/or reporter-free hPSCs further validated myogenic potential of the cells by formation of new fibers expressing human dystrophin as well as donor-derived satellite cells in NSG-mdx〈sup〉〈em〉4Cv〈/em〉〈/sup〉 mice. This study provides biological insights for myogenic differentiation of hPSCs using a double-reporter cell resource and defines an improved myogenic differentiation and purification strategy.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316711-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Tim D.D. Somerville, Yali Xu, Koji Miyabayashi, Hervé Tiriac, Cristian R. Cleary, Diogo Maia-Silva, Joseph P. Milazzo, David A. Tuveson, Christopher R. Vakoc〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative transdifferentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (ΔNp63) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. We also demonstrate that TP63-driven enhancer reprogramming promotes aggressive tumor phenotypes, including enhanced cell motility and invasion, and an accelerated growth of primary PDA tumors and metastases 〈em〉in vivo〈/em〉. This process ultimately leads to a powerful addiction of squamous PDA cells to continuous TP63 expression. Our study demonstrates the functional significance of squamous transdifferentiation in PDA and reveals TP63-based reprogramming as an experimental tool for investigating mechanisms and vulnerabilities linked to this aberrant cell fate transition.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316401-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Tao Wu, Yasunao F. Kamikawa, Mary E. Donohoe〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The pluripotent state of embryonic stem cells (ESCs) is defined by its transcriptome and epigenome. The chromatin reader Brd4 determines ESC identity. Although Brd4 regulation in gene transcription has been well described, its contribution to the chromatin landscape is less known. Here, we show that Brd4’s bromodomains partner with the histone acetyltransferase P300, increasing its enzymatic activities. Augmenting histone acetylation by Brd4-P300 interaction recruits the chromatin remodeler Brg1 altering chromatin structure. This pathway is important for maintaining the expression and chromatin patterns of pluripotency-associated genes, such as 〈em〉Oct4〈/em〉, 〈em〉Nanog〈/em〉, and the X chromosome regulatory long noncoding RNAs 〈em〉Tsix〈/em〉 and 〈em〉Xite〈/em〉. Furthermore, we show that the Brd4-P300 interaction regulates the 〈em〉de novo〈/em〉 formation of chromatin marks during ESC differentiation, as exemplified by controlling the master regulators of mesoderm formation. Collectively, we delineate the function of Brd4 in organizing the chromatin structure that contributes to gene transcriptional regulation and cell fate determination.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718315663-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Zé Henrique T.D. Góis, Adriano B.L. Tort〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Spatial navigation relies on visual landmarks as well as on self-motion information. In familiar environments, both place and grid cells maintain their firing fields in darkness, suggesting that they continuously receive information about locomotion speed required for path integration. Consistently, “speed cells” have been previously identified in the hippocampal formation and characterized in detail in the medial entorhinal cortex. Here we investigated speed-correlated firing in the hippocampus. We show that CA1 has speed cells that are stable across contexts, position in space, and time. Moreover, their speed-correlated firing occurs within theta cycles, independently of theta frequency. Interestingly, a physiological classification of cell types reveals that all CA1 speed cells are inhibitory. In fact, while speed modulates pyramidal cell activity, only the firing rate of interneurons can accurately predict locomotion speed on a sub-second timescale. These findings shed light on network models of navigation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316437-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Azahara Oliva, Antonio Fernández-Ruiz, Eliezyer Fermino de Oliveira, György Buzsáki〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Hippocampal sharp-wave ripples (SPW-Rs) support consolidation of recently acquired episodic memories and planning future actions by generating ordered neuronal sequences of previous or future experiences. SPW-Rs are characterized by several spectral components: a slow (5–15 Hz) sharp-wave, a high-frequency “ripple” oscillation (150–200 Hz), and a slow “gamma” oscillation (20–40 Hz). Using laminar hippocampal recordings and optogenetic manipulations, we dissected the origin of these spectral components. We show that increased power in the 20–40 Hz band does not reflect an entrainment of CA1 and CA3 neurons at gamma frequency but the power envelope of overlapping ripples. Spike-local field potential coupling between unit firing in CA1 and CA3 regions during SPW-Rs is lowest in the gamma band. Longer SPW-Rs are preceded by increased firing in the entorhinal cortex. Thus, fusion of SPW-Rs leads to lengthening of their duration associated with increased power in the slow gamma band without the presence of true oscillation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471831670X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 7〈/p〉 〈p〉Author(s): Xiang Zhong, Jiayao Yu, Katya Frazier, Xiaocheng Weng, Yi Li, Candace M. Cham, Kyle Dolan, Xiaorong Zhu, Nathaniel Hubert, Yun Tao, Fanfei Lin, Kristina Martinez-Guryn, Yong Huang, Tian Wang, Jianzhao Liu, Chuan He, Eugene B. Chang, Vanessa Leone〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Transcriptional regulation of circadian rhythms is essential for lipid metabolic homeostasis, disruptions of which can lead to metabolic diseases. Whether 〈em〉N〈/em〉〈sup〉6〈/sup〉-methyladenosine (m〈sup〉6〈/sup〉A) mRNA methylation impacts circadian regulation of lipid metabolism is unclear. Here, we show m〈sup〉6〈/sup〉A mRNA methylation oscillations in murine liver depend upon a functional circadian clock. Hepatic deletion of 〈em〉Bmal1〈/em〉 increases m〈sup〉6〈/sup〉A mRNA methylation, particularly of 〈em〉PPaRα〈/em〉. Inhibition of m〈sup〉6〈/sup〉A methylation via knockdown of m〈sup〉6〈/sup〉A methyltransferase METTL3 decreases 〈em〉PPaRα〈/em〉 m〈sup〉6〈/sup〉A abundance and increases 〈em〉PPaRα〈/em〉 mRNA lifetime and expression, reducing lipid accumulation in cells 〈em〉in vitro〈/em〉. Mechanistically, YTHDF2 binds to 〈em〉PPaRα〈/em〉 to mediate its mRNA stability to regulate lipid metabolism. Induction of reactive oxygen species both 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉 increases 〈em〉PPaRα〈/em〉 transcript m〈sup〉6〈/sup〉A levels, revealing a possible mechanism for circadian disruption on m〈sup〉6〈/sup〉A mRNA methylation. These data show that m〈sup〉6〈/sup〉A RNA methylation is important for circadian regulation of downstream genes and lipid metabolism, impacting metabolic outcomes.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316723-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Ming-Shun Sun, Jie Zhang, Li-Qun Jiang, Yi-Xi Pan, Jiao-Yi Tan, Fang Yu, Lin Guo, Lei Yin, Chao Shen, Hong-Bing Shu, Yu Liu〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Mediator of IRF3 activation (MITA), also known as stimulator of interferon genes (STING), plays a vital role in the innate immune responses to cytosolic dsDNA. The trafficking of MITA from the ER to perinuclear vesicles is necessary for its activation of the downstream molecules, which lead to the production of interferons and pro-inflammatory cytokines. However, the exact mechanism of MITA activation remains elusive. Here, we report that transmembrane emp24 protein transport domain containing 2 (TMED2) potentiates DNA virus-induced MITA signaling. The suppression or deletion of TMED2 markedly impairs the production of type I IFNs upon HSV-1 infection. TMED2-deficient cells harbor greater HSV-1 load than the control cells. Mechanistically, TMED2 associates with MITA only upon viral stimulation, and this process potentiates MITA activation by reinforcing its dimerization and facilitating its trafficking. These findings suggest an essential role of TMED2 in cellular IFN responses to DNA viruses.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318114-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Peace Atakpa, Nagendra Babu Thillaiappan, Stefania Mataragka, David L. Prole, Colin W. Taylor〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Inositol 1,4,5-trisphosphate (IP〈sub〉3〈/sub〉) receptors (IP〈sub〉3〈/sub〉Rs) allow extracellular stimuli to redistribute Ca〈sup〉2+〈/sup〉 from the ER to cytosol or other organelles. We show, using small interfering RNA (siRNA) and vacuolar H〈sup〉+〈/sup〉-ATPase (V-ATPase) inhibitors, that lysosomes sequester Ca〈sup〉2+〈/sup〉 released by all IP〈sub〉3〈/sub〉R subtypes, but not Ca〈sup〉2+〈/sup〉 entering cells through store-operated Ca〈sup〉2+〈/sup〉 entry (SOCE). A low-affinity Ca〈sup〉2+〈/sup〉 sensor targeted to lysosomal membranes reports large, local increases in cytosolic [Ca〈sup〉2+〈/sup〉] during IP〈sub〉3〈/sub〉-evoked Ca〈sup〉2+〈/sup〉 release, but not during SOCE. Most lysosomes associate with endoplasmic reticulum (ER) and dwell at regions populated by IP〈sub〉3〈/sub〉R clusters, but IP〈sub〉3〈/sub〉Rs do not assemble ER-lysosome contacts. Increasing lysosomal pH does not immediately prevent Ca〈sup〉2+〈/sup〉 uptake, but it causes lysosomes to slowly redistribute and enlarge, reduces their association with IP〈sub〉3〈/sub〉Rs, and disrupts Ca〈sup〉2+〈/sup〉 exchange with ER. In a “piston-like” fashion, ER concentrates cytosolic Ca〈sup〉2+〈/sup〉 and delivers it, through large-conductance IP〈sub〉3〈/sub〉Rs, to a low-affinity lysosomal uptake system. The involvement of IP〈sub〉3〈/sub〉Rs allows extracellular stimuli to regulate Ca〈sup〉2+〈/sup〉 exchange between the ER and lysosomes.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318400-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): S. Saif Hasan, Chengqun Sun, Arthur S. Kim, Yasunori Watanabe, Chun-Liang Chen, Thomas Klose, Geeta Buda, Max Crispin, Michael S. Diamond, William B. Klimstra, Michael G. Rossmann〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Alphaviruses are enveloped pathogens that cause arthritis and encephalitis. Here, we report a 4.4-Å cryoelectron microscopy (cryo-EM) structure of eastern equine encephalitis virus (EEEV), an alphavirus that causes fatal encephalitis in humans. Our analysis provides insights into viral entry into host cells. The envelope protein E2 showed a binding site for the cellular attachment factor heparan sulfate. The presence of a cryptic E2 glycan suggests how EEEV escapes surveillance by lectin-expressing myeloid lineage cells, which are sentinels of the immune system. A mechanism for nucleocapsid core release and disassembly upon viral entry was inferred based on pH changes and capsid dissociation from envelope proteins. The EEEV capsid structure showed a viral RNA genome binding site adjacent to a ribosome binding site for viral genome translation following genome release. Using five Fab-EEEV complexes derived from neutralizing antibodies, our investigation provides insights into EEEV host cell interactions and protective epitopes relevant to vaccine design.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318436-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Liya Ding, Hye-Jung Kim, Qiwei Wang, Michael Kearns, Tao Jiang, Carolynn E. Ohlson, Ben B. Li, Shaozhen Xie, Joyce F. Liu, Elizabeth H. Stover, Brooke E. Howitt, Roderick T. Bronson, Suzan Lazo, Thomas M. Roberts, Gordon J. Freeman, Panagiotis A. Konstantinopoulos, Ursula A. Matulonis, Jean J. Zhao〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉PARP inhibitors have shown promising clinical activities for patients with BRCA mutations and are changing the landscape of ovarian cancer treatment. However, the therapeutic mechanisms of action for PARP inhibition in the interaction of tumors with the tumor microenvironment and the host immune system remain unclear. We find that PARP inhibition by olaparib triggers robust local and systemic antitumor immunity involving both adaptive and innate immune responses through a STING-dependent antitumor immune response in mice bearing Brca1-deficient ovarian tumors. This effect is further augmented when olaparib is combined with PD-1 blockade. Our findings thus provide a molecular mechanism underlying antitumor activity by PARP inhibition and lay a foundation to improve therapeutic outcome for cancer patients.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318175-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): John K. Lee, Darko Bosnakovski, Erik A. Toso, Tracy Dinh, Surajit Banerjee, Thomas E. Bohl, Ke Shi, Kayo Orellana, Michael Kyba, Hideki Aihara〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Double homeobox (DUX) transcription factors are unique to eutherian mammals. DUX4 regulates expression of repetitive elements during early embryogenesis, but misexpression of DUX4 causes facioscapulohumeral muscular dystrophy (FSHD) and translocations overexpressing the DUX4 double homeodomain cause B cell leukemia. Here, we report the crystal structure of the tandem homeodomains of DUX4 bound to DNA. The homeodomains bind DNA in a head-to-head fashion, with the linker making anchoring DNA minor-groove interactions and unique protein contacts. Remarkably, despite being tandem duplicates, the DUX4 homeodomains recognize different core sequences. This results from an arginine-to-glutamate mutation, unique to primates, causing alternative positioning of a key arginine side chain in the recognition helix. Mutational studies demonstrate that this primate-specific change is responsible for the divergence in sequence recognition that likely drove coevolution of embryonically regulated repeats in primates. Our work provides a framework for understanding the endogenous function of DUX4 and its role in FSHD and cancer.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318369-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Kelsey E. Sivick, Anthony L. Desbien, Laura Hix Glickman, Gabrielle L. Reiner, Leticia Corrales, Natalie H. Surh, Thomas E. Hudson, Uyen T. Vu, Brian J. Francica, Tamara Banda, George E. Katibah, David B. Kanne, Justin J. Leong, Ken Metchette, Jacob R. Bruml, Chudi O. Ndubaku, Jeffrey M. McKenna, Yan Feng, Lianxing Zheng, Steven L. Bender〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Intratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity to uncover requirements for a T cell-driven response compatible with checkpoint inhibitors (CPIs). In contrast to high-dose tumor ablative regimens that result in systemic S100 distribution, low-dose immunogenic regimens induce local activation of tumor-specific CD8〈sup〉+〈/sup〉 effector T cells that are responsible for durable anti-tumor immunity and can be enhanced with CPIs. Both hematopoietic cell STING expression and signaling through IFNAR are required for tumor-specific T cell activation, and in the context of optimized T cell responses, TNFα is dispensable for tumor control. In a poorly immunogenic model, S100 combined with CPIs generates a survival benefit and durable protection. These results provide fundamental mechanistic insights into STING-induced anti-tumor immunity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318102-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Kathleen E. Fleming, Erin K. O’Shea〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The circadian clock of the cyanobacterium 〈em〉Synechococcus elongatus〈/em〉 PCC 7942 drives oscillations in global mRNA abundances with 24-hr periodicity under constant light conditions. The circadian clock-regulated transcription factor RpaA controls the timing of circadian gene expression, but the mechanisms underlying this control are not well understood. Here, we show that four RpaA-dependent sigma factors—RpoD2, RpoD6, RpoD5, and SigF2—are sequentially activated downstream of active RpaA and are required for proper expression of circadian mRNAs. By measuring global gene expression in strains modified to individually lack 〈em〉rpoD2〈/em〉, 〈em〉rpoD6〈/em〉, 〈em〉rpoD5〈/em〉, and 〈em〉sigF2〈/em〉, we identify how expression of circadian mRNAs, including sigma factor mRNAs, is altered in the absence of each sigma factor. Broadly, our findings suggest that a single transcription factor, RpaA, is sufficient to generate complex circadian expression patterns in part by regulating an interdependent sigma factor cascade.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318126-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Mati Mann, Arnav Mehta, Carl G. de Boer, Monika S. Kowalczyk, Kevin Lee, Pearce Haldeman, Noga Rogel, Abigail R. Knecht, Daneyal Farouq, Aviv Regev, David Baltimore〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Long-term hematopoietic stem cells (LT-HSCs) maintain hematopoietic output throughout an animal’s lifespan. However, with age, the balance is disrupted, and LT-HSCs produce a myeloid-biased output, resulting in poor immune responses to infectious challenge and the development of myeloid leukemias. Here, we show that young and aged LT-HSCs respond differently to inflammatory stress, such that aged LT-HSCs produce a cell-intrinsic, myeloid-biased expression program. Using single-cell RNA sequencing (scRNA-seq), we identify a myeloid-biased subset within the LT-HSC population (mLT-HSCs) that is prevalent among aged LT-HSCs. We identify CD61 as a marker of mLT-HSCs and show that CD61-high LT-HSCs are uniquely primed to respond to acute inflammatory challenge. We predict that several transcription factors regulate the mLT-HSCs gene program and show that 〈em〉Klf5〈/em〉, 〈em〉Ikzf1〈/em〉, and 〈em〉Stat3〈/em〉 play an important role in age-related inflammatory myeloid bias. We have therefore identified and isolated an LT-HSC subset that regulates myeloid versus lymphoid balance under inflammatory challenge and with age.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318321-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Tai An, Yi Liu, Stéphane Gourguechon, Ching C. Wang, Ziyin Li〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Protein translation in eukaryotes is cell-cycle dependent, with translation rates more robust in G1 phase of the cell cycle than in mitosis. However, whether the fundamental cell-cycle control machinery directly activates protein translation during the G1/S cell-cycle transition remains unknown. Using the early divergent eukaryote 〈em〉Trypanosoma brucei〈/em〉 as a model organism, we report that the G1 cyclin-dependent kinase CRK1 phosphorylates two translation initiation factors, eIF4E4 and PABP1, to promote the G1/S cell-cycle transition and global protein translation. Phosphorylation of eIF4E4 by CRK1 enhances binding to the m〈sup〉7〈/sup〉G cap structure and interaction with eIF4E4 and eIF4G3, and phosphorylation of PABP1 by CRK1 promotes association with the poly(A) sequence, self-interaction, and interaction with eIF4E4. These findings demonstrate that cyclin-dependent kinase-mediated regulation of translation initiation factors couples global protein translation with the G1/S cell-cycle transition.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318394-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Nicolas Panayotis, Anton Sheinin, Shachar Y. Dagan, Michael M. Tsoory, Franziska Rother, Mayur Vadhvani, Anna Meshcheriakova, Sandip Koley, Letizia Marvaldi, Didi-Andreas Song, Eitan Reuveny, Britta J. Eickholt, Enno Hartmann, Michael Bader, Izhak Michaelevski, Mike Fainzilber〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Importins mediate transport from synapse to soma and from cytoplasm to nucleus, suggesting that perturbation of importin-dependent pathways should have significant neuronal consequences. A behavioral screen on five importin α knockout lines revealed that reduced expression of importin α5 (KPNA1) in hippocampal neurons specifically decreases anxiety in mice. Re-expression of importin α5 in ventral hippocampus of knockout animals increased anxiety behaviors to wild-type levels. Hippocampal neurons lacking importin α5 reveal changes in presynaptic plasticity and modified expression of MeCP2-regulated genes, including sphingosine kinase 1 (Sphk1). Knockout of importin α5, but not importin α3 or α4, reduces MeCP2 nuclear localization in hippocampal neurons. A Sphk1 blocker reverses anxiolysis in the importin α5 knockout mouse, while pharmacological activation of sphingosine signaling has robust anxiolytic effects in wild-type animals. Thus, importin α5 influences sphingosine-sensitive anxiety pathways by regulating MeCP2 nuclear import in hippocampal neurons.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318424-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Luca Simula, Ilenia Pacella, Alessandra Colamatteo, Claudio Procaccini, Valeria Cancila, Matteo Bordi, Claudia Tregnago, Mauro Corrado, Martina Pigazzi, Vincenzo Barnaba, Claudio Tripodo, Giuseppe Matarese, Silvia Piconese, Silvia Campello〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Mitochondria are key players in the regulation of T cell biology by dynamically responding to cell needs, but how these dynamics integrate in T cells is still poorly understood. We show here that the mitochondrial pro-fission protein Drp1 fosters migration and expansion of developing thymocytes both 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉. In addition, we find that Drp1 sustains 〈em〉in vitro〈/em〉 clonal expansion and cMyc-dependent metabolic reprogramming upon activation, also regulating effector T cell numbers 〈em〉in vivo〈/em〉. Migration and extravasation defects are also exhibited in Drp1-deficient mature T cells, unveiling its crucial role in controlling both T cell recirculation in secondary lymphoid organs and accumulation at tumor sites. Moreover, the observed Drp1-dependent imbalance toward a memory-like phenotype favors T cell exhaustion in the tumor microenvironment. All of these findings support a crucial role for Drp1 in several processes during T cell development and in anti-tumor immune-surveillance.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317649-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Su Su, Anyonya R. Guntur, Daniel C. Nguyen, Shameem S. Fakory, Chad C. Doucette, Cassandra Leech, Humphrey Lotana, Matthew Kelley, Jaspreet Kohli, Julieta Martino, Sunder Sims-Lucas, Lucy Liaw, Calvin Vary, Clifford J. Rosen, Aaron C. Brown〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Molecular- and cellular-based therapies have the potential to reduce obesity-associated disease. In response to cold, beige adipocytes form in subcutaneous white adipose tissue and convert energy stored in metabolic substrates to heat, making them an attractive therapeutic target. We developed a robust method to generate a renewable source of human beige adipocytes from induced pluripotent stem cells (iPSCs). Developmentally, these cells are derived from FOXF1〈sup〉+〈/sup〉 mesoderm and progress through an expandable mural-like mesenchymal stem cell (MSC) to form mature beige adipocytes that display a thermogenically active profile. This includes expression of uncoupling protein 1 (UCP1) concomitant with increased uncoupled respiration. With this method, dysfunctional adipogenic precursors can be reprogrammed and differentiated into beige adipocytes with increased thermogenic function and anti-diabetic secretion potential. This resource can be used to (1) elucidate mechanisms that underlie the control of beige adipogenesis and (2) generate material for cellular-based therapies that target metabolic syndrome in humans.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471831800X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Xiaozhong Xiong, Markus Schober, Evelyne Tassone, Alireza Khodadadi-Jamayran, Ana Sastre-Perona, Hua Zhou, Aristotelis Tsirigos, Steven Shen, Miao Chang, Jonathan Melamed, Liliana Ossowski, Elaine L. Wilson〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉There is a considerable need to identify those individuals with prostate cancer who have indolent disease. We propose that genes that control adult stem cell homeostasis in organs with slow turnover, such as the prostate, control cancer fate. One such gene, KLF4, overexpressed in murine prostate stem cells, regulates their homeostasis, blocks malignant transformation, and controls the self-renewal of tumor-initiating cells. KLF4 loss induces the molecular features of aggressive cancer and converts PIN lesions to invasive sarcomatoid carcinomas; its re-expression 〈em〉in vivo〈/em〉 reverses this process. Bioinformatic analysis links these changes to human cancer. KLF4 and its downstream targets make up a gene signature that identifies indolent tumors and predicts recurrence-free survival. This approach may improve prognosis and identify therapeutic targets for advanced cancer.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318412-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Aishwarya Iyer-Bierhoff, Nicolai Krogh, Peter Tessarz, Thomas Ruppert, Henrik Nielsen, Ingrid Grummt〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Fibrillarin (FBL) is a dual-function nucleolar protein that catalyzes 2′-〈em〉O〈/em〉 methylation of pre-rRNA and methylation of histone H2A at glutamine 104 (H2AQ104me). The mechanisms that regulate FBL activity are unexplored. Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7. While reversible acetylation does not impact FBL-mediated pre-rRNA methylation, hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. At the onset of mitosis, nucleolar disassembly is accompanied by hyperacetylation of FBL, loss of H2AQ104me, and repression of polymerase I (Pol I) transcription. Overexpression of an acetylation-deficient, but not an acetylation-mimicking, FBL mutant restores H2AQ104me and transcriptional activity. The results reveal that SIRT7-dependent deacetylation impacts nucleolar activity by an FBL-driven circuitry that mediates cell-cycle-dependent fluctuation of rDNA transcription.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471831814X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Yi-Chien Lu, Chad Sanada, Juliana Xavier-Ferrucio, Lin Wang, Ping-Xia Zhang, H. Leighton Grimes, Meenakshi Venkatasubramanian, Kashish Chetal, Bruce Aronow, Nathan Salomonis, Diane S. Krause〈/p〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Mohammed L. Ibrahim, John D. Klement, Chunwan Lu, Priscilla S. Redd, Wei Xiao, Dafeng Yang, Darren D. Browning, Natasha M. Savage, Phillip J. Buckhaults, Herbert C. Morse, Kebin Liu〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉IL-10 functions as a suppressor of colitis and colitis-associated colon cancer, but it is also a risk locus associated with ulcerative colitis. The mechanism underlying the contrasting roles of IL-10 in inflammation and colon cancer is unknown. We report here that inflammation induces the accumulation of CD11b〈sup〉+〈/sup〉Gr1〈sup〉+〈/sup〉 myeloid-derived suppressor cells (MDSCs) that express high levels of IL-10 in colon tissue. IL-10 induces the activation of STAT3 that directly binds to the 〈em〉Dnmt1〈/em〉 and 〈em〉Dnmt3b〈/em〉 promoters to activate their expression, resulting in DNA hypermethylation at the 〈em〉Irf8〈/em〉 promoter to silence IRF8 expression in colon epithelial cells. Mice with 〈em〉Irf8〈/em〉 deleted in colonic epithelial cells exhibit significantly higher inflammation-induced tumor incidence. Human colorectal carcinomas have significantly higher DNMT1 and DNMT3b and lower IRF8 expression, and they exhibit significantly higher 〈em〉IRF8〈/em〉 promoter DNA methylation than normal colon. Our data identify the MDSC-IL-10-STAT3-DNMT3b-IRF8 pathway as a link between chronic inflammation and colon cancer initiation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318138-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 11 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 11〈/p〉 〈p〉Author(s): Yuan Cai, Christopher P. Ford〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The balance of dopamine and acetylcholine in the dorsal striatum is critical for motor and learning functions. Midbrain dopamine cells and local cholinergic interneurons (ChIs) densely innervate the striatum and have strong reciprocal actions on each other. Although dopamine inputs regulate ChIs, the functional consequences of dopamine neuron activity across dorsal striatal regions is poorly understood. Here, we find that midbrain dopamine neurons drive pauses in the firing of dorsomedial ChIs but robust bursts in dorsolateral ChIs. Pauses are mediated by dopamine D2 receptors, while bursts are driven by glutamate corelease and activation of a mGluR-mediated excitatory conductance. We find the frequency of muscarinic cholinergic transmission to medium spiny neurons is greater in the dorsomedial striatum. This regional variation in transmission is moderated by the different actions of dopamine and glutamate corelease. These results delineate a mechanism by which dopamine inputs maintain consistent levels of cholinergic activity across the dorsal striatum.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318163-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 10〈/p〉 〈p〉Author(s): Anthony J. Bainor, Siddharth Saini, Alexander Calderon, Raquel Casado-Polanco, Belén Giner-Ramirez, Claudia Moncada, David J. Cantor, Amanda Ernlund, Larisa Litovchick, Gregory David〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The mammalian DREAM complex is responsible for the transcriptional repression of hundreds of cell-cycle-related genes in quiescence. How the DREAM complex recruits chromatin-modifying entities to aid in its repression remains unknown. Using unbiased proteomics analysis, we have uncovered a robust association between the chromatin-associated Sin3B protein and the DREAM complex. We have determined that genetic inactivation of Sin3B results in the de-repression of DREAM target genes during quiescence but is insufficient to allow quiescent cells to resume proliferation. However, inactivation of APC/C〈sup〉CDH1〈/sup〉 was sufficient for Sin3B〈sup〉−/−〈/sup〉 cells, but not parental cells, to re-enter the cell cycle. These studies identify Sin3B as a transcriptional corepressor associated with the DREAM complex in quiescence and reveals a functional cooperation between E2F target repression and APC/C〈sup〉CDH1〈/sup〉 in the negative regulation of cell-cycle progression.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317704-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 10〈/p〉 〈p〉Author(s): Su Yang, Shihua Li, Xiao-Jiang Li〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Virus-mediated expression of CRISPR/Cas9 is commonly used for genome editing in animal brains to model or treat neurological diseases, but the potential neurotoxicity of overexpressing bacterial Cas9 in the mammalian brain remains unknown. Through RNA sequencing (RNA-seq) analysis, we find that virus-mediated expression of Cas9 influences the expression of genes involved in neuronal functions. Reducing the half-life of Cas9 by tagging with geminin, whose expression is regulated by the cell cycle, maintains the genome editing capacity of Cas9 but significantly alleviates neurotoxicity. Thus, modification of Cas9 by shortening its half-life can help develop CRISPR/Cas9-based therapeutic approaches for treating neurological disorders.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317650-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 10〈/p〉 〈p〉Author(s): Guillaume Bompard, Juliette van Dijk, Julien Cau, Yoann Lannay, Guillaume Marcellin, Aleksandra Lawera, Siem van der Laan, Krzysztof Rogowski〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Tubulin glutamylation is a reversible posttranslational modification that accumulates on stable microtubules (MTs). While abnormally high levels of this modification lead to a number of disorders such as male sterility, retinal degeneration, and neurodegeneration, very little is known about the molecular mechanisms underlying the regulation of glutamylase activity. Here, we found that CSAP forms a complex with TTLL5, and we demonstrate that the two proteins regulate their reciprocal abundance. Moreover, we show that CSAP increases TTLL5-mediated glutamylation and identify the TTLL5-interacting domain. Deletion of this domain leads to complete loss of CSAP activating function without impacting its MT binding. Binding of CSAP to TTLL5 promotes relocalization of TTLL5 toward MTs. Finally, we show that CSAP binds and activates all of the remaining autonomously active TTLL glutamylases. As such, we present CSAP as a major regulator of tubulin glutamylation and associated functions.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317169-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 10〈/p〉 〈p〉Author(s): Federica Mangione, Enrique Martín-Blanco〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The achievement of the final form of an individual requires not only the control of cell size and differentiation but also integrative directional cues to instruct cell movements, positions, and orientations. In 〈em〉Drosophila〈/em〉, the adult epidermis of the abdomen is created 〈em〉de novo〈/em〉 by histoblasts. As these expand and fuse, they uniformly orient along the anteroposterior axis. We found that the Dachsous/Fat/Four-jointed (Ds/Ft/Fj) pathway is key for their alignment. The refinement of the tissue-wide expression of the atypical cadherins Ds and Ft result in their polarization and directional adhesiveness. Mechanistically, the axially oriented changes in histoblasts respond to the redesign of the epithelial field. We suggest that the role of Ds/Ft/Fj in long-range oriented cell alignment is a general function and that the regulation of the expression of its components will be crucial in other morphogenetic models or during tissue repair.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317996-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 10〈/p〉 〈p〉Author(s): Benjamin M. Vincent, Daniel F. Tardiff, Jeff S. Piotrowski, Rebecca Aron, Matthew C. Lucas, Chee Yeun Chung, Helene Bacherman, YiQun Chen, Michelle Pires, Radha Subramaniam, Dimple B. Doshi, Heather Sadlish, Waseem K. Raja, Eric J. Solís, Vikram Khurana, Bertrand Le Bourdonnec, Robert H. Scannevin, Kenneth J. Rhodes〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The lack of disease-modifying treatments for neurodegenerative disease stems in part from our rudimentary understanding of disease mechanisms and the paucity of targets for therapeutic intervention. Here we used an integrated discovery paradigm to identify a new therapeutic target for diseases caused by α-synuclein (α-syn), a small lipid-binding protein that misfolds and aggregates in Parkinson’s disease and other disorders. Using unbiased phenotypic screening, we identified a series of compounds that were cytoprotective against α-syn-mediated toxicity by inhibiting the highly conserved enzyme stearoyl-CoA desaturase (SCD). Critically, reducing the levels of unsaturated membrane lipids by inhibiting SCD reduced α-syn toxicity in human induced pluripotent stem cell (iPSC) neuronal models. Taken together, these findings suggest that inhibition of fatty acid desaturation has potential as a therapeutic approach for the treatment of Parkinson’s disease and other synucleinopathies.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317741-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 10〈/p〉 〈p〉Author(s): Hongbo Ling, Lirong Peng, Jianbo Wang, Raneen Rahhal, Edward Seto〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The protein deacetylase SIRT1 (Sirtuin 1) regulates many cellular processes, including cell-cycle progression, DNA damage response, and metabolism. Although the centrosome is a key regulator of cell-cycle progression and genome stability, little is known concerning SIRT1 controlled centrosome-associated events. Here we report that the centrosome protein Plk2 is acetylated and undergoes deacetylation by SIRT1. Acetylation protects Plk2 from ubiquitination, and SIRT1-mediated deacetylation promotes ubiquitin-dependent degradation of Plk2. SIRT1 controls centriole duplication by temporally modulating centrosomal Plk2 levels. AURKA phosphorylates SIRT1 and promotes the SIRT1-Plk2 interaction in mitosis. In early-mid G〈sub〉1〈/sub〉, phosphorylated SIRT1 deacetylates and promotes Plk2 degradation. In late G〈sub〉1〈/sub〉, SIRT1 is hypophosphorylated and its affinity to Plk2 is decreased, resulting in a rapid accumulation of centrosomal Plk2, which contributes to the timely initiation of centriole duplication. Collectively, our findings uncover a critical role of SIRT1 in centriole duplication and provide a mechanistic insight into SIRT1-mediated centrosome-associated functions.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317716-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 10〈/p〉 〈p〉Author(s): Ki Eun Pyo, Chang Rok Kim, Minkyoung Lee, Jong-Seo Kim, Keun Il Kim, Sung Hee Baek〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Unc-51-like-kinase 1 (ULK1) is a target of both the mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), whose role is to facilitate the initiation of autophagy in response to starvation. Upon glucose starvation, dissociation of mTOR from ULK1 and phosphorylation by AMPK leads to the activation of ULK1 activity. Here, we provide evidence that ULK1 is the attachment of O-linked N-acetylglucosamine (O-GlcNAcylated) on the threonine 754 site by O-linked N-acetylglucosamine transferase (OGT) upon glucose starvation. ULK1 O-GlcNAcylation occurs after dephosphorylation of adjacent mTOR-dependent phosphorylation on the serine 757 site by protein phosphatase 1 (PP1) and phosphorylation by AMPK. ULK1 O-GlcNAcylation is crucial for binding and phosphorylation of ATG14L, allowing the activation of lipid kinase VPS34 and leading to the production of phosphatidylinositol-(3)-phosphate (PI(3)P), which is required for phagophore formation and initiation of autophagy. Our findings provide insights into the crosstalk between dephosphorylation and O-GlcNAcylation during autophagy and specify a molecular framework for potential therapeutic intervention in autophagy-related diseases.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318059-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 10〈/p〉 〈p〉Author(s): Elmar W. Tobi, Joost van den Heuvel, Bas J. Zwaan, L.H. Lumey, Bastiaan T. Heijmans, Tobias Uller〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉An adverse intrauterine environment is associated with long-term physiological changes in offspring. These are believed to be mediated by epigenomic marks, including DNA methylation (DNAm). Changes in DNAm are often interpreted as damage or plastic responses of the embryo. Here, we propose that stochastic DNAm variation, generated during remodeling of the epigenome after fertilization, contributes to DNAm signatures of prenatal adversity through differential survival of embryos. Using a mathematical model of re-methylation in the early embryo, we demonstrate that selection, but not plasticity, will generate a characteristic reduction in DNAm variance at loci that contribute to survival. Such a reduction in DNAm variance was apparent in a human cohort prenatally exposed to the Dutch famine, illustrating that it is possible to detect a signature of selection on epigenomic variation. Selection should be considered as a possible mechanism linking prenatal adversity to subsequent health and may have implications when evaluating interventions.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317698-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 10〈/p〉 〈p〉Author(s): Spandan V. Shah, Cordelia Manickam, Daniel R. Ram, Kyle Kroll, Hannah Itell, Sallie R. Permar, Dan H. Barouch, Nichole R. Klatt, R. Keith Reeves〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Despite burgeoning evidence demonstrating the adaptive properties of natural killer (NK) cells, mechanistic data explaining these phenomena are lacking. Following antibody sensitization, NK cells lacking the Fc receptor (FcR) signaling chain (Δg) acquire adaptive features, including robust proliferation, multifunctionality, rapid killing, and mobilization to sites of virus exposure. Using the rhesus macaque model, we demonstrate the systemic distribution of Δg NK cells expressing memory features, including downregulated Helios and Eomes. Furthermore, we find that Δg NK cells abandon typical γ-chain/Syk in lieu of CD3ζ-Zap70 signaling. FCγRIIIa (CD16) density, mucosal homing, and function are all coupled to this alternate signaling, which in itself requires priming by rhesus cytomegalovirus (rhCMV). Simian immunodeficiency virus (SIV) infections further expand gut-homing adaptive NK cells but result in pathogenic suppression of CD3ζ-Zap70 signaling and function. Herein, we provide a mechanism of virus-dependent alternative signaling that may explain the acquisition of adaptive features by primate NK cells and could be targeted for future vaccine or curative therapies.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317662-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 10〈/p〉 〈p〉Author(s): Jung Eun Han, Johannes Frasnelli, Yashar Zeighami, Kevin Larcher, Julie Boyle, Ted McConnell, Saima Malik, Marilyn Jones-Gotman, Alain Dagher〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Vulnerability to obesity includes eating in response to food cues, which acquire incentive value through conditioning. The conditioning process is largely subserved by dopamine, theorized to encode the discrepancy between expected and actual rewards known as the reward prediction error (RPE). Ghrelin is a gut-derived homeostatic hormone that triggers hunger and eating. Despite extensive evidence that ghrelin stimulates dopamine, it remains unknown in humans whether ghrelin modulates food cue learning. Here, we show using fMRI that intravenously administered ghrelin increased RPE-related activity in dopamine-responsive areas during food odor conditioning in healthy volunteers. Participants responded faster to food odor-associated cues and perceived them to be more pleasant following ghrelin injection. Ghrelin also increased functional connectivity between the hippocampus and the ventral striatum. Our work demonstrates that ghrelin promotes the ability of food cues to acquire incentive salience and has implications for the development of vulnerability to obesity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317728-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 10〈/p〉 〈p〉Author(s): Joseph P. Argus, Moses Q. Wilks, Quan D. Zhou, Wei Yuan Hsieh, Elvira Khialeeva, Xen Ping Hoi, Viet Bui, Shili Xu, Amy K. Yu, Eric S. Wang, Harvey R. Herschman, Kevin J. Williams, Steven J. Bensinger〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉It is well understood that fatty acids can be synthesized, imported, and modified to meet requisite demands in cells. However, following the movement of fatty acids through the multiplicity of these metabolic steps has remained difficult. To better address this problem, we developed Fatty Acid Source Analysis (FASA), a model that defines the contribution of synthesis, import, and elongation pathways to fatty acid homeostasis in saturated, monounsaturated, and polyunsaturated fatty acid pools. Application of FASA demonstrated that elongation can be a major contributor to cellular fatty acid content and showed that distinct pro-inflammatory stimuli (e.g., Toll-like receptors 2, 3, or 4) specifically reprogram homeostasis of fatty acids by differential utilization of synthetic and elongation pathways in macrophages. In sum, this modeling approach significantly advances our ability to interrogate cellular fatty acid metabolism and provides insight into how cells dynamically reshape their lipidomes in response to metabolic or inflammatory signals.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318047-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Mercedes Ruiz-Estevez, James Staats, Ellen Paatela, Dane Munson, Nobuko Katoku-Kikyo, Ce Yuan, Yoko Asakura, Reilly Hostager, Hiroshi Kobayashi, Atsushi Asakura, Nobuaki Kikyo〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Fkbp5 is a widely expressed peptidyl prolyl isomerase that serves as a molecular chaperone through conformational changes of binding partners. Although it regulates diverse protein functions, little is known about its roles in myogenesis. We found here that Fkbp5 plays critical roles in myoblast differentiation through two mechanisms. First, it sequesters Cdk4 within the Hsp90 storage complex and prevents the formation of the cyclin D1-Cdk4 complex, which is a major inhibitor of differentiation. Second, Fkbp5 promotes 〈em〉cis〈/em〉-〈em〉trans〈/em〉 isomerization of the Thr172-Pro173 peptide bond in Cdk4 and inhibits phosphorylation of Thr172, an essential step for Cdk4 activation. Consistent with these 〈em〉in vitro〈/em〉 findings, muscle regeneration is delayed in 〈em〉Fkbp5〈/em〉〈sup〉〈em〉−/−〈/em〉〈/sup〉 mice. The related protein Fkbp4 also sequesters Cdk4 within the Hsp90 complex but does not isomerize Cdk4 or induce Thr173 phosphorylation despite its highly similar sequence. This study demonstrates protein isomerization as a critical regulatory mechanism of myogenesis by targeting Cdk4.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317352-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Thomas B. Schaffer, Jaclyn E. Smith, Emily K. Cook, Thao Phan, Seth S. Margolis〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Protein kinase C (PKC)-dependent mechanisms promote synaptic function in the mature brain. However, the roles of PKC signaling during synapse development remain largely unknown. Investigating each brain-enriched PKC isoform in early neuronal development, we show that PKCε acutely and specifically reduces the number of dendritic spines, sites of eventual synapse formation on developing dendrites. This PKCε-mediated spine suppression is temporally restricted to immature neurons and mediated through the phosphorylation and activation of Ephexin5, a RhoA guanine nucleotide exchange factor (GEF) and inhibitor of hippocampal synapse formation. Our data suggest that PKCε acts as an early developmental inhibitor of dendritic spine formation, in contrast to its emerging pro-synaptic roles in mature brain function. Moreover, we identify a substrate of PKCε, Ephexin5, whose early-elevated expression in developing neurons may in part explain the mechanism by which PKCε plays seemingly opposing roles that depend on neuronal maturity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317340-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Peter H. Sudmant, Hyeseung Lee, Daniel Dominguez, Myriam Heiman, Christopher B. Burge〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Particular brain regions and cell populations exhibit increased susceptibility to aging-related stresses. Here, we describe the age-specific and brain-region-specific accumulation of ribosome-associated 3′ UTR RNAs that lack the 5′ UTR and open reading frame. Our study reveals that this phenomenon impacts hundreds of genes in aged D1 spiny projection neurons of the mouse striatum and also occurs in the aging human brain. Isolated 3′ UTR accumulation is tightly correlated with mitochondrial gene expression and oxidative stress, with full-length mRNA expression that is reduced but not eliminated, and with production of short 3′ UTR-encoded peptides. Depletion of the oxidation-sensitive Fe-S cluster ribosome recycling factor ABCE1 induces the accumulation of 3′ UTRs, consistent with a model in which ribosome stalling and mRNA cleavage by No-Go decay yields isolated 3′ UTR RNAs protected by ribosomes. Isolated 3′ UTR accumulation is a hallmark of brain aging, likely reflecting regional differences in metabolism and oxidative stress.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317157-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Torsten Schultz-Larsen, Andrea Lenk, Kamila Kalinowska, Lau Kræsing Vestergaard, Carsten Pedersen, Erika Isono, Hans Thordal-Christensen〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Plant “nucleotide-binding leucine-rich repeat” receptor proteins (NLRs) detect alterations in host targets of pathogen effectors and trigger immune responses. The 〈em〉Arabidopsis thaliana〈/em〉 mutant 〈em〉pen1 syp122〈/em〉 displays autoimmunity, and a mutant screen identified the deubiquitinase “associated molecule with the SH3 domain of STAM3” (AMSH3) to be required for this phenotype. AMSH3 has previously been implicated in ESCRT-mediated vacuolar targeting. Pathology experiments show that AMSH3 activity is required for immunity mediated by the CC-NLRs, RPS2 and RPM1. Co-expressing the autoactive RPM1〈sup〉D505V〈/sup〉 and the catalytically inactive ESCRT-III protein SKD1〈sup〉E232Q〈/sup〉 in 〈em〉Nicotiana benthamiana〈/em〉 supports the requirement of ESCRT-associated functions for this CC-NLR-activated immunity. Meanwhile, loss of ESCRT function in 〈em〉A. thaliana〈/em〉 is lethal, and we find that AMSH3 knockout-triggered seedling lethality is “enhanced disease susceptibility 1” (EDS1) dependent. Future studies may reveal whether AMSH3 is monitored by a TIR-NLR immunity receptor.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317571-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): SungKyoung Lee, Benjamin Cieply, Yueqin Yang, Natoya Peart, Carl Glaser, Patricia Chan, Russ P. Carstens〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The epithelial-specific splicing regulators Esrp1 and Esrp2 are required for mammalian development, including establishment of epidermal barrier functions. However, the mechanisms by which Esrp ablation causes defects in epithelial barriers remain undefined. We determined that the ablation of 〈em〉Esrp1〈/em〉 and 〈em〉Esrp2〈/em〉 impairs epithelial tight junction (TJ) integrity through loss of the epithelial isoform of Rho GTP exchange factor Arhgef11. Arhgef11 is required for the maintenance of TJs via RhoA activation and myosin light chain (MLC) phosphorylation. Ablation or depletion of 〈em〉Esrp1/2〈/em〉 or 〈em〉Arhgef11〈/em〉 inhibits MLC phosphorylation and only the epithelial Arhgef11 isoform rescues MLC phosphorylation in 〈em〉Arhgef11〈/em〉 KO epithelial cells. Mesenchymal Arhgef11 transcripts contain a C-terminal exon that binds to PAK4 and inhibits RhoA activation byArhgef11. Deletion of the mesenchymal-specific 〈em〉Arhgef11〈/em〉 exon in Esrp1/2 KO epithelial cells using CRISPR/Cas9 restored TJ function, illustrating how splicing alterations can be mechanistically linked to disease phenotypes that result from impaired functions of splicing regulators.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317182-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Dhruv Chauhan, Eva Bartok, Moritz M. Gaidt, Florian J. Bock, Jennifer Herrmann, Jens M. Seeger, Petr Broz, Roland Beckmann, Hamid Kashkar, Stephen W.G. Tait, Rolf Müller, Veit Hornung〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉IL-1β is a cytokine of pivotal importance to the orchestration of inflammatory responses. Synthesized as an inactive pro-cytokine, IL-1β requires proteolytic maturation to gain biological activity. Here, we identify intrinsic apoptosis as a non-canonical trigger of IL-1β maturation. Guided by the discovery of the immunomodulatory activity of vioprolides, cyclic peptides isolated from myxobacteria, we observe IL-1β maturation independent of canonical inflammasome pathways, yet dependent on intrinsic apoptosis. Mechanistically, vioprolides inhibit MCL-1 and BCL2, which in turn triggers BAX/BAK-dependent mitochondrial outer membrane permeabilization (MOMP). Induction of MOMP results in the release of pro-apoptotic factors initiating intrinsic apoptosis, as well as the depletion of IAPs (inhibitors of apoptosis proteins). IAP depletion, in turn, operates upstream of ripoptosome complex formation, subsequently resulting in caspase-8-dependent IL-1β maturation. These results establish the ripoptosome/caspase-8 complex as a pro-inflammatory checkpoint that senses the perturbation of mitochondrial integrity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718316917-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Haley L. Goodwill, Gabriela Manzano-Nieves, Patrick LaChance, Sana Teramoto, Shirley Lin, Chelsea Lopez, Rachel J. Stevenson, Brian B. Theyel, Christopher I. Moore, Barry W. Connors, Kevin G. Bath〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Poverty, displacement, and parental stress represent potent sources of early life stress (ELS). Stress disproportionately affects females, who are at increased risk for stress-related pathologies associated with cognitive impairment. Mechanisms underlying stress-associated cognitive impairment and enhanced risk of females remain unknown. Here, ELS is associated with impaired rule-reversal (RR) learning in females, but not males. Impaired performance was associated with decreased expression and density of interneurons expressing parvalbumin (PV+) in orbitofrontal cortex (OFC), but not other interneuron subtypes. Optogenetic silencing of PV+ interneuron activity in OFC of control mice phenocopied RR learning deficits observed in ELS females. Localization of reversal learning deficits to PV+ interneurons in OFC was confirmed by optogenetic studies in which neurons in medial prefrontal cortex (mPFC) were silenced and associated with select deficits in rule-shift learning. Sex-, cell-, and region-specific effects show altered PV+ interneuron development can be a driver of sex differences in cognitive dysfunction.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471831756X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Vera Zywitza, Aristotelis Misios, Lena Bunatyan, Thomas E. Willnow, Nikolaus Rajewsky〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Neural stem cells (NSCs) contribute to plasticity and repair of the adult brain. Niches harboring NSCs regulate stem cell self-renewal and differentiation. We used comprehensive and untargeted single-cell RNA profiling to generate a molecular cell atlas of the largest germinal region of the adult mouse brain, the subventricular zone (SVZ). We characterized 〉20 neural and non-neural cell types and gained insights into the dynamics of neurogenesis by predicting future cell states based on computational analysis of RNA kinetics. Furthermore, we applied our single-cell approach to document decreased numbers of NSCs, reduced proliferation activity of progenitors, and perturbations in Wnt and BMP signaling pathways in mice lacking LRP2, an endocytic receptor required for SVZ maintenance. Our data provide a valuable resource to study adult neurogenesis and a proof of principle for the power of single-cell RNA sequencing to elucidate neural cell-type-specific alterations in loss-of-function models.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317327-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): James E. Vince, Dominic De Nardo, Wenqing Gao, Angelina J. Vince, Cathrine Hall, Kate McArthur, Daniel Simpson, Swarna Vijayaraj, Lisa M. Lindqvist, Philippe Bouillet, Mark A. Rizzacasa, Si Ming Man, John Silke, Seth L. Masters, Guillaume Lessene, David C.S. Huang, Daniel H.D. Gray, Benjamin T. Kile, Feng Shao, Kate E. Lawlor〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Intrinsic apoptosis resulting from BAX/BAK-mediated mitochondrial membrane damage is regarded as immunologically silent. We show here that in macrophages, BAX/BAK activation results in inhibitor of apoptosis (IAP) protein degradation to promote caspase-8-mediated activation of IL-1β. Furthermore, BAX/BAK signaling induces a parallel pathway to NLRP3 inflammasome-mediated caspase-1-dependent IL-1β maturation that requires potassium efflux. Remarkably, following BAX/BAK activation, the apoptotic executioner caspases, caspase-3 and -7, act upstream of both caspase-8 and NLRP3-induced IL-1β maturation and secretion. Conversely, the pyroptotic cell death effectors gasdermin D and gasdermin E are not essential for BAX/BAK-induced IL-1β release. These findings highlight that innate immune cells undergoing BAX/BAK-mediated apoptosis have the capacity to generate pro-inflammatory signals and provide an explanation as to why IL-1β activation is often associated with cellular stress, such as during chemotherapy.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471831725X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Miljan Kuljanin, Ruth M. Elgamal, Gillian I. Bell, Dimetri Xenocostas, Anargyros Xenocostas, David A. Hess, Gilles A. Lajoie〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Human multipotent stromal cells (hMSCs) are one of the most versatile cell types used in regenerative medicine due to their ability to respond to injury. In the context of diabetes, it has been previously shown that the regenerative capacity of hMSCs is donor specific after transplantation into streptozotocin (STZ)-treated immunodeficient mice. However, 〈em〉in vivo〈/em〉 transplantation models to determine regenerative potency of hMSCs are lengthy, costly, and low throughput. Therefore, a high-throughput quantitative proteomics assay was developed to screen β cell regenerative potency of donor-derived hMSC lines. Using proteomics, we identified 16 proteins within hMSC conditioned media that effectively identify β cell regenerative hMSCs. This protein signature was validated using human islet culture assay, ELISA, and the potency was confirmed by recovery of hyperglycemia in STZ-treated mice. Herein, we demonstrated that quantitative proteomics can determine sample-specific protein signatures that can be used to classify previously uncharacterized hMSC lines for β cell regenerative clinical applications.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317297-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Kyle Wolf, Tyler Hether, Pavlo Gilchuk, Amrendra Kumar, Ahmad Rajeh, Courtney Schiebout, Julie Maybruck, R. Mark Buller, Tae-Hyuk Ahn, Sebastian Joyce, Richard J. DiPaolo〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Tracking antigen-specific T cell responses over time within individuals is difficult because of lack of knowledge of antigen-specific TCR sequences, limitations in sample size, and assay sensitivities. We hypothesized that analyses of high-throughput sequencing of TCR clonotypes could provide functional readouts of individuals’ immunological histories. Using high-throughput TCR sequencing, we develop a database of TCRβ sequences from large cohorts of mice before (naive) and after smallpox vaccination. We computationally identify 315 vaccine-associated TCR sequences (VATS) that are used to train a diagnostic classifier that distinguishes naive from vaccinated samples in mice up to 9 months post-vaccination with 〉99% accuracy. We determine that the VATS library contains virus-responsive TCRs by 〈em〉in vitro〈/em〉 expansion assays and virus-specific tetramer sorting. These data outline a platform for advancing our capabilities to identify pathogen-specific TCR sequences, which can be used to identify and quantitate low-frequency pathogen-specific TCR sequences in circulation over time with exceptional sensitivity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317558-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Aneesha G. Tewari, Sarah R. Stern, Isaac M. Oderberg, Peter W. Reddien〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The fundamental requirements for regeneration are poorly understood. Planarians can robustly regenerate all tissues after injury, involving stem cells, positional information, and a set of cellular and molecular responses collectively called the “missing tissue” or “regenerative” response. 〈em〉follistatin〈/em〉, which encodes an extracellular Activin inhibitor, is required for the missing tissue response after head amputation and for subsequent regeneration. We found that 〈em〉follistatin〈/em〉 is required for the missing tissue response regardless of the wound context, but causes regeneration failure only after head amputation. This head regeneration failure involves 〈em〉follistatin-〈/em〉mediated regulation of Wnt signaling at wounds and is not a consequence of a diminished missing tissue response. All tested contexts of regeneration, including head regeneration, could occur with a defective missing tissue response, but at a slower pace. Our findings suggest that major cellular and molecular programs induced specifically by large injuries function to accelerate regeneration but are dispensable for regeneration itself.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317339-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Iréna Lassot, Stéphan Mora, Suzanne Lesage, Barbara A. Zieba, Emmanuelle Coque, Christel Condroyer, Jozef Piotr Bossowski, Barbara Mojsa, Cecilia Marelli, Caroline Soulet, Christelle Tesson, Iria Carballo-Carbajal, Ariadna Laguna, Graziella Mangone, Miquel Vila, Alexis Brice, Solange Desagher〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Although accumulating data indicate that increased α-synuclein expression is crucial for Parkinson disease (PD), mechanisms regulating the transcription of its gene, 〈em〉SNCA〈/em〉, are largely unknown. Here, we describe a pathway regulating α-synuclein expression. Our data show that ZSCAN21 stimulates 〈em〉SNCA〈/em〉 transcription in neuronal cells and that TRIM41 is an E3 ubiquitin ligase for ZSCAN21. In contrast, TRIM17 decreases the TRIM41-mediated degradation of ZSCAN21. Silencing of 〈em〉ZSCAN21〈/em〉 and 〈em〉TRIM17〈/em〉 consistently reduces 〈em〉SNCA〈/em〉 expression, whereas 〈em〉TRIM41〈/em〉 knockdown increases it. The mRNA levels of 〈em〉TRIM17〈/em〉, 〈em〉ZSCAN21〈/em〉, and 〈em〉SNCA〈/em〉 are simultaneously increased in the midbrains of mice following MPTP treatment. In addition, rare genetic variants in 〈em〉ZSCAN21〈/em〉, 〈em〉TRIM17〈/em〉, and 〈em〉TRIM41〈/em〉 genes occur in patients with familial forms of PD. Expression of variants in 〈em〉ZSCAN21〈/em〉 and 〈em〉TRIM41〈/em〉 genes results in the stabilization of the ZSCAN21 protein. Our data thus suggest that deregulation of the TRIM17/TRIM41/ZSCAN21 pathway may be involved in the pathogenesis of PD.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317315-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Eniko Papp, Dorothy Hallberg, Gottfried E. Konecny, Daniel C. Bruhm, Vilmos Adleff, Michaël Noë, Ioannis Kagiampakis, Doreen Palsgrove, Dylan Conklin, Yasuto Kinose, James R. White, Michael F. Press, Ronny Drapkin, Hariharan Easwaran, Stephen B. Baylin, Dennis Slamon, Victor E. Velculescu, Robert B. Scharpf〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉To improve our understanding of ovarian cancer, we performed genome-wide analyses of 45 ovarian cancer cell lines. Given the challenges of genomic analyses of tumors without matched normal samples, we developed approaches for detection of somatic sequence and structural changes and integrated these with epigenetic and expression alterations. Alterations not previously implicated in ovarian cancer included amplification or overexpression of 〈em〉ASXL1〈/em〉 and 〈em〉H3F3B〈/em〉, deletion or underexpression of 〈em〉CDC73〈/em〉 and TGF-beta receptor pathway members, and rearrangements of 〈em〉YAP1-MAML2〈/em〉 and 〈em〉IKZF2-ERBB4〈/em〉. Dose-response analyses to targeted therapies revealed unique molecular dependencies, including increased sensitivity of tumors with 〈em〉PIK3CA〈/em〉 and 〈em〉PPP2R1A〈/em〉 alterations to PI3K inhibitor GNE-493, 〈em〉MYC〈/em〉 amplifications to PARP inhibitor BMN673, and 〈em〉SMAD3/4〈/em〉 alterations to MEK inhibitor MEK162. Genome-wide rearrangements provided an improved measure of sensitivity to PARP inhibition. This study provides a comprehensive and broadly accessible resource of molecular information for the development of therapeutic avenues in ovarian cancer.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317170-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Daniel B. McKim, Wenyuan Yin, Yufen Wang, Steve W. Cole, Jonathan P. Godbout, John F. Sheridan〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Psychosocial stress accelerates myelopoietic production of monocytes and neutrophils that contributes to a variety of health complications ranging from atherosclerosis to anxiety. Here, we show that social stress in mice mobilizes hematopoietic stem progenitor cells (HSPCs) from the bone marrow that enter circulation, engraft into the spleen, and establish a persistent extramedullary hematopoietic depot. These splenic progenitors actively proliferate and differentiate into multiple cell types, including monocytes, neutrophils, and erythrocytes. Splenic erythropoiesis partially abrogates stress-induced anemia. Repeated injection with isoprenaline induces progenitor mobilization to the spleen, identifying a key role for β-adrenergic signaling. Moreover, protracted splenic production of CD11b〈sup〉+〈/sup〉 cells persists for at least 24 days after the cessation of social stress. Thus, chronic stress establishes a persistent extramedullary hematopoietic depot that can modify a wide range of chronic disease processes and alter homeostasis of the bi-directional regulatory axis between the nervous and immune systems.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317248-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Raven Diacou, Yilin Zhao, Deyou Zheng, Ales Cvekl, Wei Liu〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Gene regulation of multipotent neuroretinal progenitors is partially understood. Through characterizing 〈em〉Six3〈/em〉 and 〈em〉Six6〈/em〉 double knockout retinas (DKOs), we demonstrate Six3 and Six6 are jointly required for the maintenance of multipotent neuroretinal progenitors. Phenotypes in DKOs were not found in either 〈em〉Six3〈/em〉 nulls or 〈em〉Six6〈/em〉 nulls. At the far periphery, ciliary margin (CM) markers Otx1 and Cdon together with Wnt3a and Fzd1 were ectopically upregulated, whereas neuroretinal progenitor markers Sox2, Notch1, and Otx2 were absent or reduced. At the mid periphery, multi-lineage differentiation was defective. The gene set jointly regulated by Six3 and Six6 significantly overlapped with the gene networks regulated by WNT3A, CTNNB1, POU4F2, or SOX2. Stimulation of Wnt/β-catenin signaling by either Wnt-3a or a GS3Kβ inhibitor promoted CM progenitors at the cost of neuroretinal identity at the periphery of eyecups. Therefore, Six3 and Six6 together directly or indirectly suppress Wnt/β-catenin signaling but promote retinogenic factors for the maintenance of multipotent neuroretinal progenitors.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317285-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Thomas Wild, Magda Budzowska, Susanne Hellmuth, Susana Eibes, Gopal Karemore, Marin Barisic, Olaf Stemmann, Chunaram Choudhary〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The multisubunit ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome) is essential for mitosis by promoting timely degradation of cyclin B1. APC/C is tightly regulated by the spindle assembly checkpoint (SAC), which involves MPS1 and MAD2-dependent temporal inhibition of APC/C. We analyzed the contribution of the APC/C subunits APC7 and APC16 to APC/C composition and function in human cells. APC16 is required for APC7 assembly into APC/C, whereas APC16 assembles independently of APC7. APC7 and APC16 knockout cells display no major defects in mitotic progression, cyclin B1 degradation, or SAC response, but APC/C lacking these two subunits shows reduced ubiquitylation activity 〈em〉in vitro〈/em〉. Strikingly, deletion of APC7 or APC16 is sufficient to provide synthetic viability to MAD2 deletion. ΔAPC7ΔMAD2 cells display accelerated mitosis and require SAC-independent MPS1 function for genome stability. These findings reveal that the composition of APC/C critically influences the importance of the SAC in humans.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317261-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 9〈/p〉 〈p〉Author(s): Louis S. Prahl, Patrick F. Bangasser, Lauren E. Stopfer, Mahya Hemmat, Forest M. White, Steven S. Rosenfeld, David J. Odde〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Microtubule-targeting agents (MTAs) are widely used chemotherapy drugs capable of disrupting microtubule-dependent cellular functions, such as division and migration. We show that two clinically approved MTAs, paclitaxel and vinblastine, each suppress stiffness-sensitive migration and polarization characteristic of human glioma cells on compliant hydrogels. MTAs influence microtubule dynamics and cell traction forces by nearly opposite mechanisms, the latter of which can be explained by a combination of changes in myosin motor and adhesion clutch number. Our results support a microtubule-dependent signaling-based model for controlling traction forces through a motor-clutch mechanism, rather than microtubules directly relieving tension within F-actin and adhesions. Computational simulations of cell migration suggest that increasing protrusion number also impairs stiffness-sensitive migration, consistent with experimental MTA effects. These results provide a theoretical basis for the role of microtubules and mechanisms of MTAs in controlling cell migration.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718317236-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 13〈/p〉 〈p〉Author(s): Di Chen, Wanlu Liu, Jill Zimmerman, William A. Pastor, Rachel Kim, Linzi Hosohama, Jamie Ho, Marianna Aslanyan, Joanna J. Gell, Steven E. Jacobsen, Amander T. Clark〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Human primordial germ cells (hPGCs) are the first embryonic progenitors in the germ cell lineage, yet the molecular mechanisms required for hPGC formation are not well characterized. To identify regulatory regions in hPGC development, we used the assay for transposase-accessible chromatin using sequencing (ATAC-seq) to systematically characterize regions of open chromatin in hPGCs and hPGC-like cells (hPGCLCs) differentiated from human embryonic stem cells (hESCs). We discovered regions of open chromatin unique to hPGCs and hPGCLCs that significantly overlap with TFAP2C-bound enhancers identified in the naive ground state of pluripotency. Using CRISPR/Cas9, we show that deleting the TFAP2C-bound naive enhancer at the 〈em〉OCT4〈/em〉 locus (also called 〈em〉POU5F1〈/em〉) results in impaired OCT4 expression and a negative effect on hPGCLC identity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319223-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 13〈/p〉 〈p〉Author(s): Michalis Mastri, Amanda Tracz, Christina R. Lee, Melissa Dolan, Kristopher Attwood, James G. Christensen, Song Liu, John M.L. Ebos〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) approved to treat multiple cancer types can promote metastatic disease in certain limited preclinical settings. Here, we show that stopping VEGFR TKI treatment after resistance can lead to rebound tumor growth that is driven by cellular changes resembling senescence-associated secretory phenotypes (SASPs) known to promote cancer progression. A SASP-mimicking antiangiogenic therapy-induced secretome (ATIS) was found to persist during short withdrawal periods, and blockade of known SASP regulators, including mTOR and IL-6, could blunt rebound effects. Critically, senescence hallmarks ultimately reversed after long drug withdrawal periods, suggesting that the transition to a permanent growth-arrested senescent state was incomplete and the hijacking of SASP machinery ultimately transient. These findings may account for the highly diverse and reversible cytokine changes observed in VEGF inhibitor-treated patients, and suggest senescence-targeted therapies (“senotherapeutics”)—particularly those that block SASP regulation—may improve outcomes in patients after VEGFR TKI failure.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319284-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 13〈/p〉 〈p〉Author(s): Mariateresa Fulciniti, Charles Y. Lin, Mehmet K. Samur, Michael A. Lopez, Irtisha Singh, Matthew A. Lawlor, Raphael E. Szalat, Christopher J. Ott, Herve’ Avet-Loiseau, Kenneth C. Anderson, Richard A. Young, James E. Bradner, Nikhil C. Munshi〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The relationship between promoter proximal transcription factor-associated gene expression and super-enhancer-driven transcriptional programs are not well defined. However, their distinct genomic occupancy suggests a mechanism for specific and separable gene control. We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma. We found that the transcription factor E2F1 and its heterodimerization partner DP1 represent a dependency in multiple myeloma cells. Global chromatin analysis reveals distinct regulatory axes for E2F and BETs, with E2F predominantly localized to active gene promoters of growth and/or proliferation genes and BETs disproportionately at enhancer-regulated tissue-specific genes. These two separate gene regulatory axes can be simultaneously targeted to impair the myeloma proliferative program, providing an important molecular mechanism for combination therapy. This study therefore suggests a sequestered cellular functional control that may be perturbed in cancer with potential for development of a promising therapeutic strategy.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319272-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 13〈/p〉 〈p〉Author(s): Mohammed Amir, Sweena Chaudhari, Ran Wang, Sean Campbell, Sarah A. Mosure, Laura B. Chopp, Qun Lu, Jinsai Shang, Oliver B. Pelletier, Yuanjun He, Christelle Doebelin, Michael D. Cameron, Douglas J. Kojetin, Theodore M. Kamenecka, Laura A. Solt〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉RORγt is well recognized as the lineage-defining transcription factor for T helper 17 (T〈sub〉H〈/sub〉17) cell development. However, the cell-intrinsic mechanisms that negatively regulate T〈sub〉H〈/sub〉17 cell development and autoimmunity remain poorly understood. Here, we demonstrate that the transcriptional repressor REV-ERBα is exclusively expressed in T〈sub〉H〈/sub〉17 cells, competes with RORγt for their shared DNA consensus sequence, and negatively regulates T〈sub〉H〈/sub〉17 cell development via repression of genes traditionally characterized as RORγt dependent, including 〈em〉Il17a〈/em〉. Deletion of REV-ERBα enhanced T〈sub〉H〈/sub〉17-mediated pro-inflammatory cytokine expression, exacerbating experimental autoimmune encephalomyelitis (EAE) and colitis. Treatment with REV-ERB-specific synthetic ligands, which have similar phenotypic properties as RORγ modulators, suppressed T〈sub〉H〈/sub〉17 cell development, was effective in colitis intervention studies, and significantly decreased the onset, severity, and relapse rate in several models of EAE without affecting thymic cellularity. Our results establish that REV-ERBα negatively regulates pro-inflammatory T〈sub〉H〈/sub〉17 responses 〈em〉in vivo〈/em〉 and identifies the REV-ERBs as potential targets for the treatment of T〈sub〉H〈/sub〉17-mediated autoimmune diseases.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319077-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 25, Issue 13〈/p〉 〈p〉Author(s): Manuela D’Eletto, Federica Rossin, Luca Occhigrossi, Maria Grazia Farrace, Danilo Faccenda, Radha Desai, Saverio Marchi, Giulia Refolo, Laura Falasca, Manuela Antonioli, Fabiola Ciccosanti, Gian Maria Fimia, Paolo Pinton, Michelangelo Campanella, Mauro Piacentini〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Transglutaminase type 2 (TG2) is a multifunctional enzyme that plays a key role in mitochondria homeostasis under stressful cellular conditions. TG2 interactome analysis reveals an enzyme interaction with GRP75 (glucose-regulated protein 75). GRP75 localizes in mitochondria-associated membranes (MAMs) and acts as a bridging molecule between the two organelles by assembling the IP3R-GRP75-VDAC complex, which is involved in the transport of Ca〈sup〉2+〈/sup〉 from the endoplasmic reticulum (ER) to mitochondria. We demonstrate that the TG2 and GRP75 interaction occurs in MAMs. The absence of the TG2-GRP75 interaction leads to an increase of the interaction between IP3R-3 and GRP75; a decrease of the number of ER-mitochondria contact sites; an impairment of the ER-mitochondrial Ca〈sup〉2+〈/sup〉 flux; and an altered profile of the MAM proteome. These findings indicate TG2 is a key regulatory element of the MAMs.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718318850-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉