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  • 1
    Publication Date: 2012-06-13
    Description: Myofibroblasts produce the fibrous scar in hepatic fibrosis. In the carbon tetrachloride (CCl4) model of liver fibrosis, quiescent hepatic stellate cells (HSC) are activated to become myofibroblasts. When the underlying etiological agent is removed, clinical and experimental fibrosis undergoes a remarkable regression with complete disappearance of these myofibroblasts. Although some myofibroblasts apoptose, it is unknown whether other myofibroblasts may revert to an inactive phenotype during regression of fibrosis. We elucidated the fate of HSCs/myofibroblasts during recovery from CCl4- and alcohol-induced liver fibrosis using Cre-LoxP–based genetic labeling of myofibroblasts. Here we demonstrate that half of the myofibroblasts escape apoptosis during regression of liver fibrosis, down-regulate fibrogenic genes, and acquire a phenotype similar to, but distinct from, quiescent HSCs in their ability to more rapidly reactivate into myofibroblasts in response to fibrogenic stimuli and strongly contribute to liver fibrosis. Inactivation of HSCs was associated with up-regulation of the anti-apoptotic genes Hspa1a/b, which participate in the survival of HSCs in culture and in vivo.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 2
    Publication Date: 2012-12-19
    Description: Recent studies have identified a number of transcriptional regulators, including E2A, early B-cell factor 1 (EBF1), FOXO1, and paired box gene 5 (PAX5), that promote early B-cell development. However, how this ensemble of regulators mechanistically promotes B-cell fate remains poorly understood. Here we demonstrate that B-cell development in FOXO1-deficient mice...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 3
    Publication Date: 2010-07-14
    Description: While reversible histone modifications are linked to an ever-expanding range of biological functions, the demethylases for histone H4 lysine 20 and their potential regulatory roles remain unknown. Here we report that the PHD and Jumonji C (JmjC) domain-containing protein, PHF8, while using multiple substrates, including H3K9me1/2 and H3K27me2, also functions as an H4K20me1 demethylase. PHF8 is recruited to promoters by its PHD domain based on interaction with H3K4me2/3 and controls G1-S transition in conjunction with E2F1, HCF-1 (also known as HCFC1) and SET1A (also known as SETD1A), at least in part, by removing the repressive H4K20me1 mark from a subset of E2F1-regulated gene promoters. Phosphorylation-dependent PHF8 dismissal from chromatin in prophase is apparently required for the accumulation of H4K20me1 during early mitosis, which might represent a component of the condensin II loading process. Accordingly, the HEAT repeat clusters in two non-structural maintenance of chromosomes (SMC) condensin II subunits, N-CAPD3 and N-CAPG2 (also known as NCAPD3 and NCAPG2, respectively), are capable of recognizing H4K20me1, and ChIP-Seq analysis demonstrates a significant overlap of condensin II and H4K20me1 sites in mitotic HeLa cells. Thus, the identification and characterization of an H4K20me1 demethylase, PHF8, has revealed an intimate link between this enzyme and two distinct events in cell cycle progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059551/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059551/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Wen -- Tanasa, Bogdan -- Tyurina, Oksana V -- Zhou, Tian Yuan -- Gassmann, Reto -- Liu, Wei Ting -- Ohgi, Kenneth A -- Benner, Chris -- Garcia-Bassets, Ivan -- Aggarwal, Aneel K -- Desai, Arshad -- Dorrestein, Pieter C -- Glass, Christopher K -- Rosenfeld, Michael G -- R01 CA097134/CA/NCI NIH HHS/ -- R01 CA097134-09/CA/NCI NIH HHS/ -- R01 DK018477/DK/NIDDK NIH HHS/ -- R01 DK018477-35/DK/NIDDK NIH HHS/ -- R01 DK039949/DK/NIDDK NIH HHS/ -- R01 DK039949-18/DK/NIDDK NIH HHS/ -- R01 HL065445/HL/NHLBI NIH HHS/ -- R01 NS034934/NS/NINDS NIH HHS/ -- R01 NS034934-21/NS/NINDS NIH HHS/ -- R37 DK039949/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jul 22;466(7305):508-12. doi: 10.1038/nature09272. Epub 2010 Jul 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20622854" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/metabolism ; Cell Cycle/*physiology ; Cell Line ; Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/chemistry/deficiency/genetics/*metabolism ; DNA-Binding Proteins/chemistry/metabolism ; HeLa Cells ; Histone Demethylases/chemistry/genetics/*metabolism ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/chemistry/*metabolism ; Host Cell Factor C1/genetics/metabolism ; Humans ; Lysine/*metabolism ; Methylation ; Multiprotein Complexes/chemistry/metabolism ; Phosphorylation ; Promoter Regions, Genetic ; Protein Structure, Tertiary ; Transcription Factors/chemistry/deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2011-05-17
    Description: Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell-type-specific gene expression programs, but how those enhancers are exploited to institute alternative, signal-dependent transcriptional responses remains poorly understood. Here we present evidence that cell-lineage-specific factors, such as FoxA1, can simultaneously facilitate and restrict key regulated transcription factors, exemplified by the androgen receptor (AR), to act on structurally and functionally distinct classes of enhancer. Consequently, FoxA1 downregulation, an unfavourable prognostic sign in certain advanced prostate tumours, triggers dramatic reprogramming of the hormonal response by causing a massive switch in AR binding to a distinct cohort of pre-established enhancers. These enhancers are functional, as evidenced by the production of enhancer-templated non-coding RNA (eRNA) based on global nuclear run-on sequencing (GRO-seq) analysis, with a unique class apparently requiring no nucleosome remodelling to induce specific enhancer-promoter looping and gene activation. GRO-seq data also suggest that liganded AR induces both transcription initiation and elongation. Together, these findings reveal a large repository of active enhancers that can be dynamically tuned to elicit alternative gene expression programs, which may underlie many sequential gene expression events in development, cell differentiation and disease progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117022/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117022/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Dong -- Garcia-Bassets, Ivan -- Benner, Chris -- Li, Wenbo -- Su, Xue -- Zhou, Yiming -- Qiu, Jinsong -- Liu, Wen -- Kaikkonen, Minna U -- Ohgi, Kenneth A -- Glass, Christopher K -- Rosenfeld, Michael G -- Fu, Xiang-Dong -- DK01847/DK/NIDDK NIH HHS/ -- DK074868/DK/NIDDK NIH HHS/ -- DK37949/DK/NIDDK NIH HHS/ -- GM049369/GM/NIGMS NIH HHS/ -- HG004659/HG/NHGRI NIH HHS/ -- NS34934/NS/NINDS NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P01 DK074868-05/DK/NIDDK NIH HHS/ -- P30 AG038072/AG/NIA NIH HHS/ -- R01 CA097134/CA/NCI NIH HHS/ -- R01 CA097134-10/CA/NCI NIH HHS/ -- R01 DK018477/DK/NIDDK NIH HHS/ -- R01 DK018477-35/DK/NIDDK NIH HHS/ -- R01 DK039949/DK/NIDDK NIH HHS/ -- R01 DK039949-30/DK/NIDDK NIH HHS/ -- R01 DK091183/DK/NIDDK NIH HHS/ -- R01 GM049369/GM/NIGMS NIH HHS/ -- R01 GM049369-17/GM/NIGMS NIH HHS/ -- R01 HG004659/HG/NHGRI NIH HHS/ -- R01 HG004659-03/HG/NHGRI NIH HHS/ -- R01 HL065445/HL/NHLBI NIH HHS/ -- R01 HL065445-12/HL/NHLBI NIH HHS/ -- R01 NS034934/NS/NINDS NIH HHS/ -- R01 NS034934-23/NS/NINDS NIH HHS/ -- R37 DK039949/DK/NIDDK NIH HHS/ -- R37 DK039949-28/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 May 15;474(7351):390-4. doi: 10.1038/nature10006.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21572438" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Cell Line, Tumor ; Cell Lineage ; Dihydrotestosterone/pharmacology ; Down-Regulation ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Genome, Human/genetics ; HEK293 Cells ; Hepatocyte Nuclear Factor 3-alpha/deficiency/genetics/*metabolism ; Histones/metabolism ; Humans ; Kallikreins ; Male ; Prostate-Specific Antigen ; Prostatic Neoplasms/metabolism/pathology ; RNA, Small Interfering/genetics/metabolism ; RNA, Untranslated/*genetics ; Receptors, Androgen/*metabolism ; Transcription, Genetic/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2013-06-04
    Description: Rev-Erb-alpha and Rev-Erb-beta are nuclear receptors that regulate the expression of genes involved in the control of circadian rhythm, metabolism and inflammatory responses. Rev-Erbs function as transcriptional repressors by recruiting nuclear receptor co-repressor (NCoR)-HDAC3 complexes to Rev-Erb response elements in enhancers and promoters of target genes, but the molecular basis for cell-specific programs of repression is not known. Here we present evidence that in mouse macrophages Rev-Erbs regulate target gene expression by inhibiting the functions of distal enhancers that are selected by macrophage-lineage-determining factors, thereby establishing a macrophage-specific program of repression. Remarkably, the repressive functions of Rev-Erbs are associated with their ability to inhibit the transcription of enhancer-derived RNAs (eRNAs). Furthermore, targeted degradation of eRNAs at two enhancers subject to negative regulation by Rev-Erbs resulted in reduced expression of nearby messenger RNAs, suggesting a direct role of these eRNAs in enhancer function. By precisely defining eRNA start sites using a modified form of global run-on sequencing that quantifies nascent 5' ends, we show that transfer of full enhancer activity to a target promoter requires both the sequences mediating transcription-factor binding and the specific sequences encoding the eRNA transcript. These studies provide evidence for a direct role of eRNAs in contributing to enhancer functions and suggest that Rev-Erbs act to suppress gene expression at a distance by repressing eRNA transcription.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839578/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839578/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lam, Michael T Y -- Cho, Han -- Lesch, Hanna P -- Gosselin, David -- Heinz, Sven -- Tanaka-Oishi, Yumiko -- Benner, Christopher -- Kaikkonen, Minna U -- Kim, Aneeza S -- Kosaka, Mika -- Lee, Cindy Y -- Watt, Andy -- Grossman, Tamar R -- Rosenfeld, Michael G -- Evans, Ronald M -- Glass, Christopher K -- CA014195/CA/NCI NIH HHS/ -- CA17390/CA/NCI NIH HHS/ -- CA52599/CA/NCI NIH HHS/ -- DK057978/DK/NIDDK NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK091183/DK/NIDDK NIH HHS/ -- HL088093/HL/NHLBI NIH HHS/ -- HL105278/HL/NHLBI NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P01 HL088093/HL/NHLBI NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- R01 CA052599/CA/NCI NIH HHS/ -- R01 CA173903/CA/NCI NIH HHS/ -- R01 DK018477/DK/NIDDK NIH HHS/ -- R01 DK091183/DK/NIDDK NIH HHS/ -- R01 HL105278/HL/NHLBI NIH HHS/ -- R37 DK057978/DK/NIDDK NIH HHS/ -- T32 GM007198-37/GM/NIGMS NIH HHS/ -- T32 GM008666/GM/NIGMS NIH HHS/ -- U19 DK062434/DK/NIDDK NIH HHS/ -- U19DK62434/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jun 27;498(7455):511-5. doi: 10.1038/nature12209. Epub 2013 Jun 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23728303" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Base Sequence ; Binding Sites ; Down-Regulation/*genetics ; Enhancer Elements, Genetic/*genetics ; Gene Knockdown Techniques ; Macrophages/*metabolism ; Mice ; Nuclear Receptor Subfamily 1, Group D, Member 1/deficiency/genetics/*metabolism ; Organ Specificity ; Promoter Regions, Genetic/genetics ; RNA, Messenger/genetics/metabolism ; Response Elements/genetics ; Transcription, Genetic/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2013-10-15
    Description: The mechanisms by which genetic variation affects transcription regulation and phenotypes at the nucleotide level are incompletely understood. Here we use natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation on lineage-determining and signal-specific transcription factor binding, epigenomics and transcriptional outcomes in primary macrophages from different mouse strains. We find substantial genetic evidence to support the concept that lineage-determining transcription factors define epigenetic and transcriptomic states by selecting enhancer-like regions in the genome in a collaborative fashion and facilitating binding of signal-dependent factors. This hierarchical model of transcription factor function suggests that limited sets of genomic data for lineage-determining transcription factors and informative histone modifications can be used for the prioritization of disease-associated regulatory variants.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994126/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994126/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Heinz, S -- Romanoski, C E -- Benner, C -- Allison, K A -- Kaikkonen, M U -- Orozco, L D -- Glass, C K -- 5T32DK007494/DK/NIDDK NIH HHS/ -- CA17390/CA/NCI NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK091183/DK/NIDDK NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P30 CA023100/CA/NCI NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- R01 CA173903/CA/NCI NIH HHS/ -- R01 DK091183/DK/NIDDK NIH HHS/ -- T32 AR059033/AR/NIAMS NIH HHS/ -- England -- Nature. 2013 Nov 28;503(7477):487-92. doi: 10.1038/nature12615. Epub 2013 Oct 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, Mail Code 0651, La Jolla, California 92093, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24121437" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs/genetics ; Animals ; Base Sequence ; Cell Lineage/genetics ; DNA-Binding Proteins/metabolism ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation/*genetics ; Genetic Variation/*genetics ; Histones/chemistry/metabolism ; Macrophages/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Models, Biological ; Mutation/genetics ; NF-kappa B/metabolism ; Protein Binding ; Reproducibility of Results ; Selection, Genetic/*genetics ; Transcription Factor RelA/metabolism ; Transcription Factors/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2013-10-25
    Description: Identifying cellular and molecular differences between human and non-human primates (NHPs) is essential to the basic understanding of the evolution and diversity of our own species. Until now, preserved tissues have been the main source for most comparative studies between humans, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). However, these tissue samples do not fairly represent the distinctive traits of live cell behaviour and are not amenable to genetic manipulation. We propose that induced pluripotent stem (iPS) cells could be a unique biological resource to determine relevant phenotypical differences between human and NHPs, and that those differences could have potential adaptation and speciation value. Here we describe the generation and initial characterization of iPS cells from chimpanzees and bonobos as new tools to explore factors that may have contributed to great ape evolution. Comparative gene expression analysis of human and NHP iPS cells revealed differences in the regulation of long interspersed element-1 (L1, also known as LINE-1) transposons. A force of change in mammalian evolution, L1 elements are retrotransposons that have remained active during primate evolution. Decreased levels of L1-restricting factors APOBEC3B (also known as A3B) and PIWIL2 (ref. 7) in NHP iPS cells correlated with increased L1 mobility and endogenous L1 messenger RNA levels. Moreover, results from the manipulation of A3B and PIWIL2 levels in iPS cells supported a causal inverse relationship between levels of these proteins and L1 retrotransposition. Finally, we found increased copy numbers of species-specific L1 elements in the genome of chimpanzees compared to humans, supporting the idea that increased L1 mobility in NHPs is not limited to iPS cells in culture and may have also occurred in the germ line or embryonic cells developmentally upstream to germline specification during primate evolution. We propose that differences in L1 mobility may have differentially shaped the genomes of humans and NHPs and could have continuing adaptive significance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064720/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064720/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marchetto, Maria C N -- Narvaiza, Inigo -- Denli, Ahmet M -- Benner, Christopher -- Lazzarini, Thomas A -- Nathanson, Jason L -- Paquola, Apua C M -- Desai, Keval N -- Herai, Roberto H -- Weitzman, Matthew D -- Yeo, Gene W -- Muotri, Alysson R -- Gage, Fred H -- AI074967/AI/NIAID NIH HHS/ -- GM084317/GM/NIGMS NIH HHS/ -- HG004659/HG/NHGRI NIH HHS/ -- MH08848/MH/NIMH NIH HHS/ -- MH094753/MH/NIMH NIH HHS/ -- NS075449/NS/NINDS NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- R01 MH088485/MH/NIMH NIH HHS/ -- R01 MH094753/MH/NIMH NIH HHS/ -- R01 MH095741/MH/NIMH NIH HHS/ -- R01 NS075449/NS/NINDS NIH HHS/ -- England -- Nature. 2013 Nov 28;503(7477):525-9. doi: 10.1038/nature12686. Epub 2013 Oct 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24153179" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins/metabolism ; Cell Line ; Cell Shape ; Cytidine Deaminase/metabolism ; Evolution, Molecular ; Genome, Human/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Karyotyping ; Long Interspersed Nucleotide Elements/*genetics ; Mice, Nude ; Pan paniscus/*genetics/metabolism ; Pan troglodytes/*genetics/metabolism ; Pluripotent Stem Cells/cytology/*metabolism ; RNA, Messenger/analysis/genetics ; Sequence Analysis, RNA ; Species Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2016-04-30
    Description: The host innate immune response is the first line of defense against pathogens and is orchestrated by the concerted expression of genes induced by microbial stimuli. Deregulated expression of these genes is linked to the initiation and progression of diseases associated with exacerbated inflammation. Here, we identify Topoisomerase 1 (Top1) as a positive regulator of RNA polymerase II (RNAPII) transcriptional activity at pathogen-induced genes. Depletion or chemical inhibition of Top1 suppresses the host response against Influenza and Ebola viruses as well as bacterial products. As a result, therapeutic pharmacological inhibition of Top1 protects mice from death in experimental models of lethal inflammation. Our results indicate that Top1 inhibition could be used as therapy against life threatening infections characterized by an acutely exacerbated immune response.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rialdi, Alex -- Campisi, Laura -- Zhao, Nan -- Lagda, Arvin Cesar -- Pietzsch, Colette -- Ho, Jessica Sook Yuin -- Martinez-Gil, Luis -- Fenouil, Romain -- Chen, Xiaoting -- Edwards, Megan -- Metreveli, Giorgi -- Jordan, Stefan -- Peralta, Zuleyma -- Munoz-Fontela, Cesar -- Bouvier, Nicole -- Merad, Miriam -- Jin, Jian -- Weirauch, Matthew -- Heinz, Sven -- Benner, Chris -- van Bakel, Harm -- Basler, Chris -- Garcia-Sastre, Adolfo -- Bukreyev, Alexander -- Marazzi, Ivan -- New York, N.Y. -- Science. 2016 Apr 28. pii: aad7993.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. ; Department of Pathology, Microbiology, and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA. ; Laboratory of Methyltransferases in Development and Disease, Institute of Molecular and Cell Biology, Singapore. ; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Biochemistry and Molecular Biology, Universitat de Valencia, Valencia, Spain. ; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. ; Center for Autoimmune Genomics and Etiology (CAGE) and Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. ; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. ; Department of Oncological Sciences, Tisch Cancer Institute and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. ; Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany. ; Department of Structural and Chemical Biology, Department of Oncological Sciences, and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. ; Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. ; Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. ; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. ivan.marazzi@mssm.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27127234" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2015-05-07
    Description: Pluripotency, the ability to generate any cell type of the body, is an evanescent attribute of embryonic cells. Transitory pluripotent cells can be captured at different time points during embryogenesis and maintained as embryonic stem cells or epiblast stem cells in culture. Since ontogenesis is a dynamic process in both space and time, it seems counterintuitive that these two temporal states represent the full spectrum of organismal pluripotency. Here we show that by modulating culture parameters, a stem-cell type with unique spatial characteristics and distinct molecular and functional features, designated as region-selective pluripotent stem cells (rsPSCs), can be efficiently obtained from mouse embryos and primate pluripotent stem cells, including humans. The ease of culturing and editing the genome of human rsPSCs offers advantages for regenerative medicine applications. The unique ability of human rsPSCs to generate post-implantation interspecies chimaeric embryos may facilitate our understanding of early human development and evolution.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Jun -- Okamura, Daiji -- Li, Mo -- Suzuki, Keiichiro -- Luo, Chongyuan -- Ma, Li -- He, Yupeng -- Li, Zhongwei -- Benner, Chris -- Tamura, Isao -- Krause, Marie N -- Nery, Joseph R -- Du, Tingting -- Zhang, Zhuzhu -- Hishida, Tomoaki -- Takahashi, Yuta -- Aizawa, Emi -- Kim, Na Young -- Lajara, Jeronimo -- Guillen, Pedro -- Campistol, Josep M -- Esteban, Concepcion Rodriguez -- Ross, Pablo J -- Saghatelian, Alan -- Ren, Bing -- Ecker, Joseph R -- Izpisua Belmonte, Juan Carlos -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 May 21;521(7552):316-21. doi: 10.1038/nature14413. Epub 2015 May 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Salk Institute for Biological Studies, Gene Expression Laboratory, La Jolla, California 92037, USA. ; 1] Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] The Salk Institute for Biological Studies, Genomic Analysis Laboratory, La Jolla, California 92037, USA. ; The Salk Institute for Biological Studies, Genomic Analysis Laboratory, La Jolla, California 92037, USA. ; The Salk Institute for Biological Studies, Integrated Genomics, La Jolla, California 92037, USA. ; Ludwig Institute for Cancer Research, University of California, San Diego School of Medicine, Department of Cellular and Molecular Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653, USA. ; 1] The Salk Institute for Biological Studies, Gene Expression Laboratory, La Jolla, California 92037, USA [2] Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8577, Japan. ; Grado en Medicina, Universidad Catolica, San Antonio de Murcia, Campus de los Jeronimos, 135, Guadalupe 30107, Spain. ; 1] Grado en Medicina, Universidad Catolica, San Antonio de Murcia, Campus de los Jeronimos, 135, Guadalupe 30107, Spain [2] Fundacion Pedro Guillen, Clinica Cemtro, Avenida Ventisquero de la Condesa, 42, 28035 Madrid, Spain. ; Hospital Clinic of Barcelona, Carrer Villarroel, 170, 08036 Barcelona, Spain. ; University of California, Davis, Davis, California 95616, USA. ; The Salk Institute for Biological Studies, Peptide Biology Laboratory, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25945737" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Culture Techniques/methods ; Cell Line ; *Chimera ; Embryonic Stem Cells/cytology ; Female ; Germ Layers/cytology ; Humans ; Induced Pluripotent Stem Cells/cytology ; Male ; Mice ; Pan troglodytes ; Pluripotent Stem Cells/*cytology/metabolism ; Regenerative Medicine ; Species Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Journal of Magnetic Resonance (1969) 63 (1985), S. 125-132 
    ISSN: 0022-2364
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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