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  • 1
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    Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: Voltage-gated CaV1.2 channels (L-type calcium channel alpha1C subunits) are critical mediators of transcription-dependent neural plasticity. Whether these channels signal via the influx of calcium ion (Ca(2+)), voltage-dependent conformational change (VDeltaC), or a combination of the two has thus far been equivocal. We fused CaV1.2 to a ligand-gated Ca(2+)-permeable channel, enabling independent control of localized Ca(2+) and VDeltaC signals. This revealed an unexpected dual requirement: Ca(2+) must first mobilize actin-bound Ca(2+)/calmodulin-dependent protein kinase II, freeing it for subsequent VDeltaC-mediated accumulation. Neither signal alone sufficed to activate transcription. Signal order was crucial: Efficiency peaked when Ca(2+) preceded VDeltaC by 10 to 20 seconds. CaV1.2 VDeltaC synergistically augmented signaling by N-methyl-d-aspartate receptors. Furthermore, VDeltaC mistuning correlated with autistic symptoms in Timothy syndrome. Thus, nonionic VDeltaC signaling is vital to the function of CaV1.2 in synaptic and neuropsychiatric processes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Boxing -- Tadross, Michael R -- Tsien, Richard W -- New York, N.Y. -- Science. 2016 Feb 19;351(6275):863-7. doi: 10.1126/science.aad3647.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience and Physiology and New York University Neuroscience Institute, New York, NY 10016, USA. ; Department of Molecular and Cellular Physiology, Beckman Center, School of Medicine, Stanford University, Stanford, CA 94305, USA. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. tadrossm@janelia.hhmi.org. ; Department of Neuroscience and Physiology and New York University Neuroscience Institute, New York, NY 10016, USA. Department of Molecular and Cellular Physiology, Beckman Center, School of Medicine, Stanford University, Stanford, CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912895" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/genetics/metabolism ; Calcium Channel Blockers/pharmacology ; Calcium Channels, L-Type/chemistry/*metabolism ; *Calcium Signaling ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism ; Cells, Cultured ; Cyclic AMP Response Element-Binding Protein/metabolism ; *Gene Expression Regulation ; HEK293 Cells ; Hippocampus/cytology ; Humans ; Long QT Syndrome/genetics/metabolism ; Neuronal Plasticity/*genetics ; Neurons/drug effects/*metabolism ; Nimodipine/pharmacology ; Protein Conformation/drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism ; Synapses/metabolism ; Syndactyly/genetics/metabolism
    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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  • 2
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    NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-01-28
    Description: Inflammasomes are intracellular protein complexes that drive the activation of inflammatory caspases. So far, four inflammasomes involving NLRP1, NLRP3, NLRC4 and AIM2 have been described that recruit the common adaptor protein ASC to activate caspase-1, leading to the secretion of mature IL-1beta and IL-18 proteins. The NLRP3 inflammasome has been implicated in the pathogenesis of several acquired inflammatory diseases as well as cryopyrin-associated periodic fever syndromes (CAPS) caused by inherited NLRP3 mutations. Potassium efflux is a common step that is essential for NLRP3 inflammasome activation induced by many stimuli. Despite extensive investigation, the molecular mechanism leading to NLRP3 activation in response to potassium efflux remains unknown. Here we report the identification of NEK7, a member of the family of mammalian NIMA-related kinases (NEK proteins), as an NLRP3-binding protein that acts downstream of potassium efflux to regulate NLRP3 oligomerization and activation. In the absence of NEK7, caspase-1 activation and IL-1beta release were abrogated in response to signals that activate NLRP3, but not NLRC4 or AIM2 inflammasomes. NLRP3-activating stimuli promoted the NLRP3-NEK7 interaction in a process that was dependent on potassium efflux. NLRP3 associated with the catalytic domain of NEK7, but the catalytic activity of NEK7 was shown to be dispensable for activation of the NLRP3 inflammasome. Activated macrophages formed a high-molecular-mass NLRP3-NEK7 complex, which, along with ASC oligomerization and ASC speck formation, was abrogated in the absence of NEK7. NEK7 was required for macrophages containing the CAPS-associated NLRP3(R258W) activating mutation to activate caspase-1. Mouse chimaeras reconstituted with wild-type, Nek7(-/-) or Nlrp3(-/-) haematopoietic cells showed that NEK7 was required for NLRP3 inflammasome activation in vivo. These studies demonstrate that NEK7 is an essential protein that acts downstream of potassium efflux to mediate NLRP3 inflammasome assembly and activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Yuan -- Zeng, Melody Y -- Yang, Dahai -- Motro, Benny -- Nunez, Gabriel -- R01AI063331/AI/NIAID NIH HHS/ -- R01DK091191/DK/NIDDK NIH HHS/ -- T32 HL007517/HL/NHLBI NIH HHS/ -- T32DK094775/DK/NIDDK NIH HHS/ -- T32HL007517/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Feb 18;530(7590):354-7. doi: 10.1038/nature16959. Epub 2016 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. ; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26814970" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins/deficiency/genetics/metabolism ; Biocatalysis ; Carrier Proteins/chemistry/genetics/*metabolism ; Caspase 1/metabolism ; Catalytic Domain ; Cells, Cultured ; Cryopyrin-Associated Periodic Syndromes/genetics ; Enzyme Activation ; HEK293 Cells ; Humans ; Inflammasomes/*chemistry/*metabolism ; Interleukin-1beta/secretion ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Potassium/*metabolism ; Protein Binding ; Protein Multimerization ; Protein-Serine-Threonine Kinases/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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  • 3
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    Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-01-23
    Description: Differentiated macrophages can self-renew in tissues and expand long term in culture, but the gene regulatory mechanisms that accomplish self-renewal in the differentiated state have remained unknown. Here we show that in mice, the transcription factors MafB and c-Maf repress a macrophage-specific enhancer repertoire associated with a gene network that controls self-renewal. Single-cell analysis revealed that, in vivo, proliferating resident macrophages can access this network by transient down-regulation of Maf transcription factors. The network also controls embryonic stem cell self-renewal but is associated with distinct embryonic stem cell-specific enhancers. This indicates that distinct lineage-specific enhancer platforms regulate a shared network of genes that control self-renewal potential in both stem and mature cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Soucie, Erinn L -- Weng, Ziming -- Geirsdottir, Laufey -- Molawi, Kaaweh -- Maurizio, Julien -- Fenouil, Romain -- Mossadegh-Keller, Noushine -- Gimenez, Gregory -- VanHille, Laurent -- Beniazza, Meryam -- Favret, Jeremy -- Berruyer, Carole -- Perrin, Pierre -- Hacohen, Nir -- Andrau, J-C -- Ferrier, Pierre -- Dubreuil, Patrice -- Sidow, Arend -- Sieweke, Michael H -- P01AG036695/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):aad5510. doi: 10.1126/science.aad5510. Epub 2016 Jan 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. Centre de Recherche en Cancerologie de Marseille, INSERM (U1068), CNRS (U7258), Universite Aix-Marseille (UM105), Marseille, France. sieweke@ciml.univ-mrs.fr erinn.soucie@inserm.fr arend@stanford.edu. ; Department of Pathology, Stanford University, Stanford, CA 94305-5324, USA. ; Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. ; Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, 10 Robert-Rossle-Strasse, 13125 Berlin, Germany. ; Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA. ; Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. Institut de Genetique Moleculaire de Montpellier, CNRS UMR 5535, 1919 Route de Mende, 34293 Montpellier, France. ; Centre de Recherche en Cancerologie de Marseille, INSERM (U1068), CNRS (U7258), Universite Aix-Marseille (UM105), Marseille, France. ; Department of Pathology, Stanford University, Stanford, CA 94305-5324, USA. Department of Genetics, Stanford University, Stanford, CA 94305, USA. sieweke@ciml.univ-mrs.fr erinn.soucie@inserm.fr arend@stanford.edu. ; Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, 10 Robert-Rossle-Strasse, 13125 Berlin, Germany. sieweke@ciml.univ-mrs.fr erinn.soucie@inserm.fr arend@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26797145" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation/*genetics ; Cell Lineage/*genetics ; Cell Proliferation ; Cells, Cultured ; Down-Regulation ; Embryonic Stem Cells/*cytology ; Enhancer Elements, Genetic/*physiology ; *Gene Expression Regulation ; Gene Regulatory Networks ; Macrophages/*cytology ; MafB Transcription Factor/metabolism ; Mice ; Proto-Oncogene Proteins c-maf/metabolism ; Single-Cell Analysis ; Transcriptional Activation
    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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  • 4
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    Insulator dysfunction and oncogene activation in IDH mutant gliomas (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-12-25
    Description: Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a new onco-metabolite, 2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes catalyse a key step in the removal of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), although the functional importance of this altered epigenetic state remains unclear. Here we show that human IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent partially restores insulator function and downregulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wild-type gliomaspheres upregulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Flavahan, William A -- Drier, Yotam -- Liau, Brian B -- Gillespie, Shawn M -- Venteicher, Andrew S -- Stemmer-Rachamimov, Anat O -- Suva, Mario L -- Bernstein, Bradley E -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Jan 7;529(7584):110-4. doi: 10.1038/nature16490. Epub 2015 Dec 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. ; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26700815" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Binding Sites ; CRISPR-Cas Systems/genetics ; Cell Cycle Proteins/metabolism ; Cell Proliferation/drug effects ; Cell Transformation, Neoplastic/drug effects ; Cells, Cultured ; Chromatin/drug effects/genetics/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; CpG Islands/genetics ; DNA Methylation/drug effects/genetics ; Down-Regulation/drug effects ; Enhancer Elements, Genetic/genetics ; Epigenesis, Genetic/drug effects ; *Gene Expression Regulation, Neoplastic/drug effects ; Glioma/drug therapy/*enzymology/*genetics/pathology ; Glutarates/metabolism ; Humans ; Insulator Elements/drug effects/*genetics ; Isocitrate Dehydrogenase/chemistry/*genetics/metabolism ; Mutation/*genetics ; Oncogenes/*genetics ; Phenotype ; Protein Binding ; Receptor, Platelet-Derived Growth Factor alpha/genetics ; Repressor Proteins/metabolism ; Up-Regulation
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Competition between DNA methylation and transcription factors determines binding of NRF1 (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-12-18
    Description: Eukaryotic transcription factors (TFs) are key determinants of gene activity, yet they bind only a fraction of their corresponding DNA sequence motifs in any given cell type. Chromatin has the potential to restrict accessibility of binding sites; however, in which context chromatin states are instructive for TF binding remains mainly unknown. To explore the contribution of DNA methylation to constrained TF binding, we mapped DNase-I-hypersensitive sites in murine stem cells in the presence and absence of DNA methylation. Methylation-restricted sites are enriched for TF motifs containing CpGs, especially for those of NRF1. In fact, the TF NRF1 occupies several thousand additional sites in the unmethylated genome, resulting in increased transcription. Restoring de novo methyltransferase activity initiates remethylation at these sites and outcompetes NRF1 binding. This suggests that binding of DNA-methylation-sensitive TFs relies on additional determinants to induce local hypomethylation. In support of this model, removal of neighbouring motifs in cis or of a TF in trans causes local hypermethylation and subsequent loss of NRF1 binding. This competition between DNA methylation and TFs in vivo reveals a case of cooperativity between TFs that acts indirectly via DNA methylation. Methylation removal by methylation-insensitive factors enables occupancy of methylation-sensitive factors, a principle that rationalizes hypomethylation of regulatory regions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Domcke, Silvia -- Bardet, Anais Flore -- Adrian Ginno, Paul -- Hartl, Dominik -- Burger, Lukas -- Schubeler, Dirk -- England -- Nature. 2015 Dec 24;528(7583):575-9. doi: 10.1038/nature16462. Epub 2015 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH 4058 Basel, Switzerland. ; University of Basel, Faculty of Sciences, Petersplatz 1, CH 4003 Basel, Switzerland. ; Swiss Institute of Bioinformatics, Maulbeerstrasse 66, CH 4058 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26675734" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Binding, Competitive ; Cells, Cultured ; Chromatin/chemistry/genetics/*metabolism ; *DNA Methylation ; Deoxyribonuclease I/metabolism ; Genome/genetics ; Humans ; Mice ; Mouse Embryonic Stem Cells/metabolism ; Nuclear Respiratory Factor 1/*metabolism ; Protein Binding ; 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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  • 6
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    The histone chaperone CAF-1 safeguards somatic cell identity (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-12-15
    Description: Cellular differentiation involves profound remodelling of chromatic landscapes, yet the mechanisms by which somatic cell identity is subsequently maintained remain incompletely understood. To further elucidate regulatory pathways that safeguard the somatic state, we performed two comprehensive RNA interference (RNAi) screens targeting chromatin factors during transcription-factor-mediated reprogramming of mouse fibroblasts to induced pluripotent stem cells (iPS cells). Subunits of the chromatin assembly factor-1 (CAF-1) complex, including Chaf1a and Chaf1b, emerged as the most prominent hits from both screens, followed by modulators of lysine sumoylation and heterochromatin maintenance. Optimal modulation of both CAF-1 and transcription factor levels increased reprogramming efficiency by several orders of magnitude and facilitated iPS cell formation in as little as 4 days. Mechanistically, CAF-1 suppression led to a more accessible chromatin structure at enhancer elements early during reprogramming. These changes were accompanied by a decrease in somatic heterochromatin domains, increased binding of Sox2 to pluripotency-specific targets and activation of associated genes. Notably, suppression of CAF-1 also enhanced the direct conversion of B cells into macrophages and fibroblasts into neurons. Together, our findings reveal the histone chaperone CAF-1 to be a novel regulator of somatic cell identity during transcription-factor-induced cell-fate transitions and provide a potential strategy to modulate cellular plasticity in a regenerative setting.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheloufi, Sihem -- Elling, Ulrich -- Hopfgartner, Barbara -- Jung, Youngsook L -- Murn, Jernej -- Ninova, Maria -- Hubmann, Maria -- Badeaux, Aimee I -- Euong Ang, Cheen -- Tenen, Danielle -- Wesche, Daniel J -- Abazova, Nadezhda -- Hogue, Max -- Tasdemir, Nilgun -- Brumbaugh, Justin -- Rathert, Philipp -- Jude, Julian -- Ferrari, Francesco -- Blanco, Andres -- Fellner, Michaela -- Wenzel, Daniel -- Zinner, Marietta -- Vidal, Simon E -- Bell, Oliver -- Stadtfeld, Matthias -- Chang, Howard Y -- Almouzni, Genevieve -- Lowe, Scott W -- Rinn, John -- Wernig, Marius -- Aravin, Alexei -- Shi, Yang -- Park, Peter J -- Penninger, Josef M -- Zuber, Johannes -- Hochedlinger, Konrad -- P50-HG007735/HG/NHGRI NIH HHS/ -- R01 HD058013-06/HD/NICHD NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Dec 10;528(7581):218-24. doi: 10.1038/nature15749.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA. ; Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. ; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), A-1030 Vienna, Austria. ; Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), A-1030 Vienna, Austria. ; Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA. ; California Institute of Technology, Division of Biology and Biological Engineering, Pasadena, California 91125, USA. ; Institute for Stem Cell Biology and Regenerative Medicine, Department of Pathology and Department of Bioengineering, Stanford University, Stanford, California 94305, USA. ; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA. ; Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; The Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, Department of Cell Biology, NYU School of Medicine, New York, New York 10016, USA. ; Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA. ; Centre de Recherche, Institut Curie, 75248 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26659182" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cells, Cultured ; Cellular Reprogramming/*genetics ; Chromatin/metabolism ; Chromatin Assembly Factor-1/antagonists & inhibitors/genetics/*metabolism ; Gene Expression Regulation/genetics ; Heterochromatin/metabolism ; Mice ; Nucleosomes/metabolism ; RNA Interference ; Transduction, Genetic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    Barcoding reveals complex clonal dynamics of de novo transformed human mammary cells (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-12-04
    Description: Most human breast cancers have diversified genomically and biologically by the time they become clinically evident. Early events involved in their genesis and the cellular context in which these events occur have thus been difficult to characterize. Here we present the first formal evidence of the shared and independent ability of basal cells and luminal progenitors, isolated from normal human mammary tissue and transduced with a single oncogene (KRAS(G12D)), to produce serially transplantable, polyclonal, invasive ductal carcinomas within 8 weeks of being introduced either subrenally or subcutaneously into immunodeficient mice. DNA barcoding of the initial cells revealed a dramatic change in the numbers and sizes of clones generated from them within 2 weeks, and the first appearance of many 'new' clones in tumours passaged into secondary recipients. Both primary and secondary tumours were phenotypically heterogeneous and primary tumours were categorized transcriptionally as 'normal-like'. This system challenges previous concepts that carcinogenesis in normal human epithelia is necessarily a slow process requiring the acquisition of multiple driver mutations. It also presents the first description of initial events that accompany the genesis and evolution of malignant human mammary cell populations, thereby contributing new understanding of the rapidity with which heterogeneity in their properties can develop.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nguyen, Long V -- Pellacani, Davide -- Lefort, Sylvain -- Kannan, Nagarajan -- Osako, Tomo -- Makarem, Maisam -- Cox, Claire L -- Kennedy, William -- Beer, Philip -- Carles, Annaick -- Moksa, Michelle -- Bilenky, Misha -- Balani, Sneha -- Babovic, Sonja -- Sun, Ivan -- Rosin, Miriam -- Aparicio, Samuel -- Hirst, Martin -- Eaves, Connie J -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2015 Dec 10;528(7581):267-71. doi: 10.1038/nature15742. Epub 2015 Dec 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada. ; Department of Medical Genetics, University of British Columbia, Vancouver, British ColumbiaV6T 2B5, Canada. ; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada. ; Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada. ; Centre for High-Throughput Biology, Department of Microbiology &Immunology, University of British Columbia, 2125 East Mall, Vancouver, British Columbia V6T 1Z4, Canada. ; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada. ; Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada. ; Cancer Control Unit, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26633636" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/genetics/*physiopathology ; Carcinoma, Ductal, Breast/genetics/*physiopathology ; Cell Lineage/genetics ; *Cell Transformation, Neoplastic ; Cells, Cultured ; DNA Barcoding, Taxonomic ; Female ; Gene Expression Profiling ; Heterografts ; Humans ; Lentivirus/genetics ; Mammary Glands, Human/cytology/*physiopathology ; Mice ; Mice, Inbred Strains ; Mice, SCID ; Proto-Oncogene Proteins/genetics ; Time Factors ; Transduction, Genetic ; ras Proteins/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
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    F508 CFTR interactome remodelling promotes rescue of cystic fibrosis (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-12-01
    Description: Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (F508 CFTR) is the major cause of cystic fibrosis, one of the most common inherited childhood diseases. The mutated CFTR anion channel is not fully glycosylated and shows minimal activity in bronchial epithelial cells of patients with cystic fibrosis. Low temperature or inhibition of histone deacetylases can partly rescue F508 CFTR cellular processing defects and function. A favourable change of F508 CFTR protein-protein interactions was proposed as a mechanism of rescue; however, CFTR interactome dynamics during temperature shift and inhibition of histone deacetylases are unknown. Here we report the first comprehensive analysis of the CFTR and F508 CFTR interactome and its dynamics during temperature shift and inhibition of histone deacetylases. By using a novel deep proteomic analysis method, we identify 638 individual high-confidence CFTR interactors and discover a F508 deletion-specific interactome, which is extensively remodelled upon rescue. Detailed analysis of the interactome remodelling identifies key novel interactors, whose loss promote F508 CFTR channel function in primary cystic fibrosis epithelia or which are critical for CFTR biogenesis. Our results demonstrate that global remodelling of F508 CFTR interactions is crucial for rescue, and provide comprehensive insight into the molecular disease mechanisms of cystic fibrosis caused by deletion of F508.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pankow, Sandra -- Bamberger, Casimir -- Calzolari, Diego -- Martinez-Bartolome, Salvador -- Lavallee-Adam, Mathieu -- Balch, William E -- Yates, John R 3rd -- 5R01HL079442-08/HL/NHLBI NIH HHS/ -- HHSN268201000035C/PHS HHS/ -- P01 AG031097/AG/NIA NIH HHS/ -- P01AG031097/AG/NIA NIH HHS/ -- P41 GM103533/GM/NIGMS NIH HHS/ -- R01 HL079442/HL/NHLBI NIH HHS/ -- R01DK051870/DK/NIDDK NIH HHS/ -- R01HL095524/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Dec 24;528(7583):510-6. doi: 10.1038/nature15729. Epub 2015 Nov 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. ; Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26618866" target="_blank"〉PubMed〈/a〉
    Keywords: Bronchi/cytology ; Cells, Cultured ; Cystic Fibrosis/genetics/*metabolism/*therapy ; Cystic Fibrosis Transmembrane Conductance ; Regulator/biosynthesis/*genetics/*metabolism ; Epithelial Cells/chemistry/metabolism ; Gene Knockdown Techniques ; Glycosylation ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/deficiency/metabolism ; Humans ; Mutant Proteins/genetics/metabolism ; Protein Folding ; Protein Interaction Mapping ; *Protein Interaction Maps ; Proteomics ; RNA Interference ; RNAi Therapeutics ; Sequence Deletion/*genetics ; Temperature
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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    Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-11-26
    Description: Copy number variations have been frequently associated with developmental delay, intellectual disability and autism spectrum disorders. MECP2 duplication syndrome is one of the most common genomic rearrangements in males and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and early death. The broad range of deficits caused by methyl-CpG-binding protein 2 (MeCP2) overexpression poses a daunting challenge to traditional biochemical-pathway-based therapeutic approaches. Accordingly, we sought strategies that directly target MeCP2 and are amenable to translation into clinical therapy. The first question that we addressed was whether the neurological dysfunction is reversible after symptoms set in. Reversal of phenotypes in adult symptomatic mice has been demonstrated in some models of monogenic loss-of-function neurological disorders, including loss of MeCP2 in Rett syndrome, indicating that, at least in some cases, the neuroanatomy may remain sufficiently intact so that correction of the molecular dysfunction underlying these disorders can restore healthy physiology. Given the absence of neurodegeneration in MECP2 duplication syndrome, we propose that restoration of normal MeCP2 levels in MECP2 duplication adult mice would rescue their phenotype. By generating and characterizing a conditional Mecp2-overexpressing mouse model, here we show that correction of MeCP2 levels largely reverses the behavioural, molecular and electrophysiological deficits. We also reduced MeCP2 using an antisense oligonucleotide strategy, which has greater translational potential. Antisense oligonucleotides are small, modified nucleic acids that can selectively hybridize with messenger RNA transcribed from a target gene and silence it, and have been successfully used to correct deficits in different mouse models. We find that antisense oligonucleotide treatment induces a broad phenotypic rescue in adult symptomatic transgenic MECP2 duplication mice (MECP2-TG), and corrected MECP2 levels in lymphoblastoid cells from MECP2 duplication patients in a dose-dependent manner.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sztainberg, Yehezkel -- Chen, Hong-mei -- Swann, John W -- Hao, Shuang -- Tang, Bin -- Wu, Zhenyu -- Tang, Jianrong -- Wan, Ying-Wooi -- Liu, Zhandong -- Rigo, Frank -- Zoghbi, Huda Y -- 1U54HD083092/HD/NICHD NIH HHS/ -- 5P30HD024064/HD/NICHD NIH HHS/ -- 5R01NS057819/NS/NINDS NIH HHS/ -- P30 HD024064/HD/NICHD NIH HHS/ -- R01 NS057819/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Dec 3;528(7580):123-6. doi: 10.1038/nature16159. Epub 2015 Nov 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA. ; The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA. ; Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, California 92010, USA. ; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26605526" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Attachment Sites, Microbiological/genetics ; Cells, Cultured ; Disease Models, Animal ; Electroencephalography ; Gene Dosage/*genetics ; Gene Duplication/genetics ; *Gene Knockdown Techniques ; Genes, Duplicate/*genetics ; Humans ; Integrases/genetics/metabolism ; Mental Retardation, X-Linked/*genetics/physiopathology ; Methyl-CpG-Binding Protein 2/*genetics/metabolism ; Mice ; Mice, Transgenic ; Oligonucleotides, Antisense/*genetics ; *Phenotype
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    FGF signalling regulates bone growth through autophagy (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-11-26
    Description: Skeletal growth relies on both biosynthetic and catabolic processes. While the role of the former is clearly established, how the latter contributes to growth-promoting pathways is less understood. Macroautophagy, hereafter referred to as autophagy, is a catabolic process that plays a fundamental part in tissue homeostasis. We investigated the role of autophagy during bone growth, which is mediated by chondrocyte rate of proliferation, hypertrophic differentiation and extracellular matrix (ECM) deposition in growth plates. Here we show that autophagy is induced in growth-plate chondrocytes during post-natal development and regulates the secretion of type II collagen (Col2), the major component of cartilage ECM. Mice lacking the autophagy related gene 7 (Atg7) in chondrocytes experience endoplasmic reticulum storage of type II procollagen (PC2) and defective formation of the Col2 fibrillary network in the ECM. Surprisingly, post-natal induction of chondrocyte autophagy is mediated by the growth factor FGF18 through FGFR4 and JNK-dependent activation of the autophagy initiation complex VPS34-beclin-1. Autophagy is completely suppressed in growth plates from Fgf18(-/-) embryos, while Fgf18(+/-) heterozygous and Fgfr4(-/-) mice fail to induce autophagy during post-natal development and show decreased Col2 levels in the growth plate. Strikingly, the Fgf18(+/-) and Fgfr4(-/-) phenotypes can be rescued in vivo by pharmacological activation of autophagy, pointing to autophagy as a novel effector of FGF signalling in bone. These data demonstrate that autophagy is a developmentally regulated process necessary for bone growth, and identify FGF signalling as a crucial regulator of autophagy in chondrocytes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cinque, Laura -- Forrester, Alison -- Bartolomeo, Rosa -- Svelto, Maria -- Venditti, Rossella -- Montefusco, Sandro -- Polishchuk, Elena -- Nusco, Edoardo -- Rossi, Antonio -- Medina, Diego L -- Polishchuk, Roman -- De Matteis, Maria Antonietta -- Settembre, Carmine -- England -- Nature. 2015 Dec 10;528(7581):272-5. doi: 10.1038/nature16063. Epub 2015 Nov 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei, 34, 80078 Pozzuoli (NA), Italy. ; Dulbecco Telethon Institute, Via Campi Flegrei, 34, 80078 Pozzuoli (NA), Italy. ; Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Via Pansini 5, 80131 Naples, Italy. ; Department of Molecular Medicine, Biochemistry Unit, University of Pavia, 27100 Pavia, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26595272" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy/genetics/*physiology ; Bone Development/genetics/*physiology ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; Chondrocytes/cytology/metabolism ; Collagen Type II/secretion ; Embryo, Mammalian ; Extracellular Matrix/genetics ; Fibroblast Growth Factors/*genetics/metabolism ; Growth Plate/cytology/metabolism ; MAP Kinase Signaling System ; Mice ; Microtubule-Associated Proteins/genetics/metabolism ; Receptor, Fibroblast Growth Factor, Type 4/genetics/metabolism ; *Signal Transduction
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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