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  • Animals  (6)
  • Air Transportation and Safety
  • Nature Publishing Group (NPG)  (6)
  • 2015-2019  (6)
  • 1995-1999
  • 1
    Publication Date: 2015-02-18
    Description: Enhancers regulate spatiotemporal gene expression and impart cell-specific transcriptional outputs that drive cell identity. Super-enhancers (SEs), also known as stretch-enhancers, are a subset of enhancers especially important for genes associated with cell identity and genetic risk of disease. CD4(+) T cells are critical for host defence and autoimmunity. Here we analysed maps of mouse T-cell SEs as a non-biased means of identifying key regulatory nodes involved in cell specification. We found that cytokines and cytokine receptors were the dominant class of genes exhibiting SE architecture in T cells. Nonetheless, the locus encoding Bach2, a key negative regulator of effector differentiation, emerged as the most prominent T-cell SE, revealing a network in which SE-associated genes critical for T-cell biology are repressed by BACH2. Disease-associated single-nucleotide polymorphisms for immune-mediated disorders, including rheumatoid arthritis, were highly enriched for T-cell SEs versus typical enhancers or SEs in other cell lineages. Intriguingly, treatment of T cells with the Janus kinase (JAK) inhibitor tofacitinib disproportionately altered the expression of rheumatoid arthritis risk genes with SE structures. Together, these results indicate that genes with SE architecture in T cells encompass a variety of cytokines and cytokine receptors but are controlled by a 'guardian' transcription factor, itself endowed with an SE. Thus, enumeration of SEs allows the unbiased determination of key regulatory nodes in T cells, which are preferentially modulated by pharmacological intervention.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409450/" 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/PMC4409450/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vahedi, Golnaz -- Kanno, Yuka -- Furumoto, Yasuko -- Jiang, Kan -- Parker, Stephen C J -- Erdos, Michael R -- Davis, Sean R -- Roychoudhuri, Rahul -- Restifo, Nicholas P -- Gadina, Massimo -- Tang, Zhonghui -- Ruan, Yijun -- Collins, Francis S -- Sartorelli, Vittorio -- O'Shea, John J -- 105663/Z/14/Z/Wellcome Trust/United Kingdom -- R01 CA186714/CA/NCI NIH HHS/ -- ZIA AR041159-07/Intramural NIH HHS/ -- England -- Nature. 2015 Apr 23;520(7548):558-62. doi: 10.1038/nature14154. Epub 2015 Feb 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. ; Translational Immunology Section, NIAMS, NIH, Bethesda, Maryland 20892, USA. ; Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA. ; Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA. ; The Jackson Laboratory for Genomic Medicine and Department of Genetic and Development Biology, University of Connecticut, Farmington, Connecticut 06030, USA. ; Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25686607" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arthritis, Rheumatoid/*genetics/immunology/pathology ; Basic-Leucine Zipper Transcription Factors/metabolism ; Cell Differentiation/genetics ; Cell Lineage/genetics ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation/genetics ; Genetic Predisposition to Disease/genetics ; Janus Kinase 3/antagonists & inhibitors ; Mice ; Mice, Inbred C57BL ; Piperidines/pharmacology ; Pyrimidines/pharmacology ; Pyrroles/pharmacology ; RNA, Untranslated/genetics ; T-Lymphocytes, Helper-Inducer/immunology/*metabolism/*pathology ; Transcription, Genetic/genetics ; p300-CBP 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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  • 2
    Publication Date: 2015-07-01
    Description: Patterns of amino acid conservation have served as a tool for understanding protein evolution. The same principles have also found broad application in human genomics, driven by the need to interpret the pathogenic potential of variants in patients. Here we performed a systematic comparative genomics analysis of human disease-causing missense variants. We found that an appreciable fraction of disease-causing alleles are fixed in the genomes of other species, suggesting a role for genomic context. We developed a model of genetic interactions that predicts most of these to be simple pairwise compensations. Functional testing of this model on two known human disease genes revealed discrete cis amino acid residues that, although benign on their own, could rescue the human mutations in vivo. This approach was also applied to ab initio gene discovery to support the identification of a de novo disease driver in BTG2 that is subject to protective cis-modification in more than 50 species. Finally, on the basis of our data and models, we developed a computational tool to predict candidate residues subject to compensation. Taken together, our data highlight the importance of cis-genomic context as a contributor to protein evolution; they provide an insight into the complexity of allele effect on phenotype; and they are likely to assist methods for predicting allele pathogenicity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537371/" 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/PMC4537371/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jordan, Daniel M -- Frangakis, Stephan G -- Golzio, Christelle -- Cassa, Christopher A -- Kurtzberg, Joanne -- Task Force for Neonatal Genomics -- Davis, Erica E -- Sunyaev, Shamil R -- Katsanis, Nicholas -- R01 DK072301/DK/NIDDK NIH HHS/ -- R01 DK075972/DK/NIDDK NIH HHS/ -- R01 DK095721/DK/NIDDK NIH HHS/ -- R01 EY021872/EY/NEI NIH HHS/ -- R01 GM078598/GM/NIGMS NIH HHS/ -- R01 HD042601/HD/NICHD NIH HHS/ -- R01 MH101244/MH/NIMH NIH HHS/ -- R01DK072301/DK/NIDDK NIH HHS/ -- R01DK075972/DK/NIDDK NIH HHS/ -- R01EY021872/EY/NEI NIH HHS/ -- R01HD04260/HD/NICHD NIH HHS/ -- U01 HG006500/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 Aug 13;524(7564):225-9. doi: 10.1038/nature14497. Epub 2015 Jun 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. ; Center for Human Disease Modeling, Duke University, Durham, North Carolina 27701, USA. ; Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation, Duke University, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26123021" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics ; Alleles ; Animals ; Disease/*genetics ; Evolution, Molecular ; Genome, Human/genetics ; *Genomics ; Humans ; Immediate-Early Proteins/genetics ; Microcephaly/genetics ; Mutation, Missense/*genetics ; Phenotype ; Proteins/genetics ; Sequence Alignment ; Suppression, Genetic/*genetics ; Tumor Suppressor Proteins/genetics
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2016-04-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nardone, Roland M -- MacLeod, Roderick A F -- Capes-Davis, Amanda -- England -- Nature. 2016 Apr 21;532(7599):313.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27127813" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; DNA Contamination ; Databases, Factual ; *Disease Models, Animal ; Guidelines as Topic ; Heterografts/*standards ; Humans ; National Cancer Institute (U.S.) ; Neoplasms/*pathology ; Quality Control ; Reproducibility of Results ; United States ; Xenograft Model Antitumor Assays/*standards
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2016-01-28
    Description: Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752392/" 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/PMC4752392/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sekar, Aswin -- Bialas, Allison R -- de Rivera, Heather -- Davis, Avery -- Hammond, Timothy R -- Kamitaki, Nolan -- Tooley, Katherine -- Presumey, Jessy -- Baum, Matthew -- Van Doren, Vanessa -- Genovese, Giulio -- Rose, Samuel A -- Handsaker, Robert E -- Schizophrenia Working Group of the Psychiatric Genomics Consortium -- Daly, Mark J -- Carroll, Michael C -- Stevens, Beth -- McCarroll, Steven A -- R01 HG006855/HG/NHGRI NIH HHS/ -- R01 MH077139/MH/NIMH NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- U01 MH105641/MH/NIMH NIH HHS/ -- England -- Nature. 2016 Feb 11;530(7589):177-83. doi: 10.1038/nature16549. Epub 2016 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; MD-PhD Program, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA. ; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26814963" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Amino Acid Sequence ; Animals ; Axons/metabolism ; Base Sequence ; Brain/metabolism/pathology ; Complement C4/chemistry/*genetics ; Complement Pathway, Classical ; Dendrites/metabolism ; Gene Dosage/genetics ; Gene Expression Regulation/genetics ; Genetic Predisposition to Disease/*genetics ; Genetic Variation/*genetics ; Haplotypes/genetics ; Humans ; Major Histocompatibility Complex/genetics ; Mice ; Models, Animal ; Neuronal Plasticity/genetics/physiology ; Polymorphism, Single Nucleotide/genetics ; RNA, Messenger/analysis/genetics ; Risk Factors ; Schizophrenia/*genetics/pathology ; Synapses/metabolism
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  • 5
    Publication Date: 2016-05-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Davis, Andrew R -- Broad, Allison -- England -- Nature. 2016 May 5;533(7601):36. doi: 10.1038/533036a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Wollongong, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27147022" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Aquatic Organisms ; Biodiversity ; Conservation of Natural Resources/*methods/trends ; *Ecosystem ; Ships/*methods
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  • 6
    Publication Date: 2015-12-18
    Description: Understanding how ecological communities are organized and how they change through time is critical to predicting the effects of climate change. Recent work documenting the co-occurrence structure of modern communities found that most significant species pairs co-occur less frequently than would be expected by chance. However, little is known about how co-occurrence structure changes through time. Here we evaluate changes in plant and animal community organization over geological time by quantifying the co-occurrence structure of 359,896 unique taxon pairs in 80 assemblages spanning the past 300 million years. Co-occurrences of most taxon pairs were statistically random, but a significant fraction were spatially aggregated or segregated. Aggregated pairs dominated from the Carboniferous period (307 million years ago) to the early Holocene epoch (11,700 years before present), when there was a pronounced shift to more segregated pairs, a trend that continues in modern assemblages. The shift began during the Holocene and coincided with increasing human population size and the spread of agriculture in North America. Before the shift, an average of 64% of significant pairs were aggregated; after the shift, the average dropped to 37%. The organization of modern and late Holocene plant and animal assemblages differs fundamentally from that of assemblages over the past 300 million years that predate the large-scale impacts of humans. Our results suggest that the rules governing the assembly of communities have recently been changed by human activity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lyons, S Kathleen -- Amatangelo, Kathryn L -- Behrensmeyer, Anna K -- Bercovici, Antoine -- Blois, Jessica L -- Davis, Matt -- DiMichele, William A -- Du, Andrew -- Eronen, Jussi T -- Faith, J Tyler -- Graves, Gary R -- Jud, Nathan -- Labandeira, Conrad -- Looy, Cindy V -- McGill, Brian -- Miller, Joshua H -- Patterson, David -- Pineda-Munoz, Silvia -- Potts, Richard -- Riddle, Brett -- Terry, Rebecca -- Toth, Aniko -- Ulrich, Werner -- Villasenor, Amelia -- Wing, Scott -- Anderson, Heidi -- Anderson, John -- Waller, Donald -- Gotelli, Nicholas J -- England -- Nature. 2016 Jan 7;529(7584):80-3. doi: 10.1038/nature16447. Epub 2015 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Paleobiology, National Museum of Natural History, Smithsonian Institution, Washington DC 20013, USA. ; Department of Environmental Science and Biology, The College at Brockport - SUNY, Brockport, New York 14420, USA. ; School of Natural Sciences, University of California, Merced, 5200 North Lake Road, Merced, California 95343, USA. ; Department of Geology and Geophysics, Yale University, New Haven, Connecticut 06520, USA. ; Hominid Paleobiology Doctoral Program, Center for the Advanced Study of Hominid Paleobiology, Department of Anthropology, George Washington University, Washington DC 20052, USA. ; Department of Geosciences and Geography, University of Helsinki, PO Box 64, 00014 University of Helsinki, Finland. ; School of Social Science, The University of Queensland, Brisbane, Queensland 4072, Australia. ; Department of Vertebrate Zoology, National Museum of Natural History, Smithsonian Institution, Washington DC 20013, USA. ; Center for Macroecology, Evolution and Climate, University of Copenhagen, Copenhagen 2100, Denmark. ; Biological Sciences Graduate Program, University of Maryland, College Park, Maryland 20742, USA. ; Florida Museum of Natural History, University of Florida, Gainsville, Florida 32611, USA. ; Department of Entomology, University of Maryland College Park, College Park, Maryland 20742, USA. ; Key Lab of Insect Evolution and Environmental Changes, Capital Normal University, Beijing 100048, China. ; Department of Integrative Biology and Museum of Paleontology, University of California Berkeley, Berkeley, California 94720, USA. ; School Biology and Ecology &Sustainability Solutions Initiative, University of Maine, Orono, Maine 04469, USA. ; Department of Geology, University of Cincinnati, Cincinnati, Ohio 45221, USA. ; Department of Biological Sciences, Macquarie University, Sydney, New South Wales 2109, Australia. ; Department of Anthropology, Human Origins Program, National Museum of Natural History, Smithsonian Institution, Washington DC 20013, USA. ; School of Life Sciences, University of Nevada-Las Vegas, Las Vegas, Nevada 89154, USA. ; Department of Integrative Biology, Oregon State University, Corvallis, Oregon 97331, USA. ; Chair of Ecology and Biogeography, Nicolaus Copernicus University, Lwowska 1, 87-100 Torun, Poland. ; Evolutionary Studies Institute, University of the Witwatersrand, Jorissen Street, Braamfontein, Johannesburg 2001, South Africa. ; Department of Botany, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA. ; Department of Biology, University of Vermont, Burlington, Vermont 05405, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26675730" target="_blank"〉PubMed〈/a〉
    Keywords: Agriculture/*history ; Animals ; *Ecosystem ; History, Ancient ; Human Activities/*history ; Humans ; North America ; *Plant Physiological Phenomena ; Population Dynamics ; Time Factors
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