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  • 1
    Publication Date: 2011-01-25
    Description: Common fragile sites have long been identified by cytogeneticists as chromosomal regions prone to breakage upon replication stress. They are increasingly recognized to be preferential targets for oncogene-induced DNA damage in pre-neoplastic lesions and hotspots for chromosomal rearrangements in various cancers. Common fragile site instability was attributed to the fact that they contain sequences prone to form secondary structures that may impair replication fork movement, possibly leading to fork collapse resulting in DNA breaks. Here we show, in contrast to this view, that the fragility of FRA3B--the most active common fragile site in human lymphocytes--does not rely on fork slowing or stalling but on a paucity of initiation events. Indeed, in lymphoblastoid cells, but not in fibroblasts, initiation events are excluded from a FRA3B core extending approximately 700 kilobases, which forces forks coming from flanking regions to cover long distances in order to complete replication. We also show that origins of the flanking regions fire in mid-S phase, leaving the site incompletely replicated upon fork slowing. Notably, FRA3B instability is specific to cells showing this particular initiation pattern. The fact that both origin setting and replication timing are highly plastic in mammalian cells explains the tissue specificity of common fragile site instability we observed. Thus, we propose that common fragile sites correspond to the latest initiation-poor regions to complete replication in a given cell type. For historical reasons, common fragile sites have been essentially mapped in lymphocytes. Therefore, common fragile site contribution to chromosomal rearrangements in tumours should be reassessed after mapping fragile sites in the cell type from which each tumour originates.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Letessier, Anne -- Millot, Gael A -- Koundrioukoff, Stephane -- Lachages, Anne-Marie -- Vogt, Nicolas -- Hansen, R Scott -- Malfoy, Bernard -- Brison, Olivier -- Debatisse, Michelle -- England -- Nature. 2011 Feb 3;470(7332):120-3. doi: 10.1038/nature09745. Epub 2011 Jan 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Curie, Centre de Recherche, 26 rue d'Ulm, 75248 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21258320" target="_blank"〉PubMed〈/a〉
    Keywords: Acid Anhydride Hydrolases/*genetics ; Cell Line ; Chromosome Breakage ; Chromosome Fragile Sites/*genetics ; Chromosome Fragility/genetics/*physiology ; DNA Replication/genetics/*physiology ; Fibroblasts ; Genes, Tumor Suppressor ; Genetic Loci/genetics ; Humans ; Lymphocytes/metabolism ; Models, Biological ; Neoplasm Proteins/*genetics ; Organ Specificity ; Replication Origin/*genetics
    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: 2014-11-21
    Description: The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining approximately 8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is approximately 95% similar with that derived from human TF footprints. However, only approximately 20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405208/" 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/PMC4405208/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stergachis, Andrew B -- Neph, Shane -- Sandstrom, Richard -- Haugen, Eric -- Reynolds, Alex P -- Zhang, Miaohua -- Byron, Rachel -- Canfield, Theresa -- Stelhing-Sun, Sandra -- Lee, Kristen -- Thurman, Robert E -- Vong, Shinny -- Bates, Daniel -- Neri, Fidencio -- Diegel, Morgan -- Giste, Erika -- Dunn, Douglas -- Vierstra, Jeff -- Hansen, R Scott -- Johnson, Audra K -- Sabo, Peter J -- Wilken, Matthew S -- Reh, Thomas A -- Treuting, Piper M -- Kaul, Rajinder -- Groudine, Mark -- Bender, M A -- Borenstein, Elhanan -- Stamatoyannopoulos, John A -- FDK095678A/PHS HHS/ -- R01 EY021482/EY/NEI NIH HHS/ -- R37 DK044746/DK/NIDDK NIH HHS/ -- R37DK44746/DK/NIDDK NIH HHS/ -- RC2 HG005654/HG/NHGRI NIH HHS/ -- RC2HG005654/HG/NHGRI NIH HHS/ -- T32 GM007266/GM/NIGMS NIH HHS/ -- U01ES01156/ES/NIEHS NIH HHS/ -- U54 HG007010/HG/NHGRI NIH HHS/ -- U54HG004592/HG/NHGRI NIH HHS/ -- U54HG007010/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Nov 20;515(7527):365-70. doi: 10.1038/nature13972.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. ; Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; 1] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA [2] Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ; Department of Biological Structure, University of Washington, Seattle, Washington 98195, USA. ; Department of Comparative Medicine, University of Washington, Seattle, Washington 98195, USA. ; 1] Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA [2] Division of Radiation Oncology, University of Washington, Seattle, Washington 98195, USA. ; 1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA [2] Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. ; 1] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA [2] Department of Computer Science and Engineering, University of Washington, Seattle, Washington 98102, USA [3] Santa Fe Institute, Santa Fe, New Mexico 87501, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409825" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Conserved Sequence/*genetics ; DNA Footprinting ; *Evolution, Molecular ; Gene Expression Regulation, Developmental/genetics ; Gene Regulatory Networks/genetics ; Humans ; Mammals/*genetics ; Mice ; Regulatory Sequences, Nucleic Acid/*genetics ; Transcription Factors/*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
    Publication Date: 2014-11-21
    Description: The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266106/" 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/PMC4266106/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yue, Feng -- Cheng, Yong -- Breschi, Alessandra -- Vierstra, Jeff -- Wu, Weisheng -- Ryba, Tyrone -- Sandstrom, Richard -- Ma, Zhihai -- Davis, Carrie -- Pope, Benjamin D -- Shen, Yin -- Pervouchine, Dmitri D -- Djebali, Sarah -- Thurman, Robert E -- Kaul, Rajinder -- Rynes, Eric -- Kirilusha, Anthony -- Marinov, Georgi K -- Williams, Brian A -- Trout, Diane -- Amrhein, Henry -- Fisher-Aylor, Katherine -- Antoshechkin, Igor -- DeSalvo, Gilberto -- See, Lei-Hoon -- Fastuca, Meagan -- Drenkow, Jorg -- Zaleski, Chris -- Dobin, Alex -- Prieto, Pablo -- Lagarde, Julien -- Bussotti, Giovanni -- Tanzer, Andrea -- Denas, Olgert -- Li, Kanwei -- Bender, M A -- Zhang, Miaohua -- Byron, Rachel -- Groudine, Mark T -- McCleary, David -- Pham, Long -- Ye, Zhen -- Kuan, Samantha -- Edsall, Lee -- Wu, Yi-Chieh -- Rasmussen, Matthew D -- Bansal, Mukul S -- Kellis, Manolis -- Keller, Cheryl A -- Morrissey, Christapher S -- Mishra, Tejaswini -- Jain, Deepti -- Dogan, Nergiz -- Harris, Robert S -- Cayting, Philip -- Kawli, Trupti -- Boyle, Alan P -- Euskirchen, Ghia -- Kundaje, Anshul -- Lin, Shin -- Lin, Yiing -- Jansen, Camden -- Malladi, Venkat S -- Cline, Melissa S -- Erickson, Drew T -- Kirkup, Vanessa M -- Learned, Katrina -- Sloan, Cricket A -- Rosenbloom, Kate R -- Lacerda de Sousa, Beatriz -- Beal, Kathryn -- Pignatelli, Miguel -- Flicek, Paul -- Lian, Jin -- Kahveci, Tamer -- Lee, Dongwon -- Kent, W James -- Ramalho Santos, Miguel -- Herrero, Javier -- Notredame, Cedric -- Johnson, Audra -- Vong, Shinny -- Lee, Kristen -- Bates, Daniel -- Neri, Fidencio -- Diegel, Morgan -- Canfield, Theresa -- Sabo, Peter J -- Wilken, Matthew S -- Reh, Thomas A -- Giste, Erika -- Shafer, Anthony -- Kutyavin, Tanya -- Haugen, Eric -- Dunn, Douglas -- Reynolds, Alex P -- Neph, Shane -- Humbert, Richard -- Hansen, R Scott -- De Bruijn, Marella -- Selleri, Licia -- Rudensky, Alexander -- Josefowicz, Steven -- Samstein, Robert -- Eichler, Evan E -- Orkin, Stuart H -- Levasseur, Dana -- Papayannopoulou, Thalia -- Chang, Kai-Hsin -- Skoultchi, Arthur -- Gosh, Srikanta -- Disteche, Christine -- Treuting, Piper -- Wang, Yanli -- Weiss, Mitchell J -- Blobel, Gerd A -- Cao, Xiaoyi -- Zhong, Sheng -- Wang, Ting -- Good, Peter J -- Lowdon, Rebecca F -- Adams, Leslie B -- Zhou, Xiao-Qiao -- Pazin, Michael J -- Feingold, Elise A -- Wold, Barbara -- Taylor, James -- Mortazavi, Ali -- Weissman, Sherman M -- Stamatoyannopoulos, John A -- Snyder, Michael P -- Guigo, Roderic -- Gingeras, Thomas R -- Gilbert, David M -- Hardison, Ross C -- Beer, Michael A -- Ren, Bing -- Mouse ENCODE Consortium -- 095908/Wellcome Trust/United Kingdom -- 1U54HG007004/HG/NHGRI NIH HHS/ -- 3RC2HG005602/HG/NHGRI NIH HHS/ -- F31CA165863/CA/NCI NIH HHS/ -- F32HL110473/HL/NHLBI NIH HHS/ -- GM083337/GM/NIGMS NIH HHS/ -- GM085354/GM/NIGMS NIH HHS/ -- K99HL119617/HL/NHLBI NIH HHS/ -- P01 GM085354/GM/NIGMS NIH HHS/ -- P01 HL064190/HL/NHLBI NIH HHS/ -- P01 HL110860/HL/NHLBI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30 CA045508/CA/NCI NIH HHS/ -- R01 DK065806/DK/NIDDK NIH HHS/ -- R01 DK096266/DK/NIDDK NIH HHS/ -- R01 ES024992/ES/NIEHS NIH HHS/ -- R01 EY021482/EY/NEI NIH HHS/ -- R01 GM083337/GM/NIGMS NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- R01 HG007175/HG/NHGRI NIH HHS/ -- R01 HG007348/HG/NHGRI NIH HHS/ -- R01 HG007354/HG/NHGRI NIH HHS/ -- R01DK065806/DK/NIDDK NIH HHS/ -- R01HD043997-09/HD/NICHD NIH HHS/ -- R01HG003991/HG/NHGRI NIH HHS/ -- R37 DK044746/DK/NIDDK NIH HHS/ -- R56 DK065806/DK/NIDDK NIH HHS/ -- RC2 HG005573/HG/NHGRI NIH HHS/ -- RC2HG005573/HG/NHGRI NIH HHS/ -- T32 GM081739/GM/NIGMS NIH HHS/ -- U01 HL099656/HL/NHLBI NIH HHS/ -- U01 HL099993/HL/NHLBI NIH HHS/ -- U54 HG006997/HG/NHGRI NIH HHS/ -- U54 HG006998/HG/NHGRI NIH HHS/ -- U54 HG007004/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Nov 20;515(7527):355-64. doi: 10.1038/nature13992.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Ludwig Institute for Cancer Research and University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, USA. [2] Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania 17033, USA. ; Department of Genetics, Stanford University, 300 Pasteur Drive, MC-5477 Stanford, California 94305, USA. ; Bioinformatics and Genomics, Centre for Genomic Regulation (CRG) and UPF, Doctor Aiguader, 88, 08003 Barcelona, Catalonia, Spain. ; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. ; Center for Comparative Genomics and Bioinformatics, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Department of Biological Science, 319 Stadium Drive, Florida State University, Tallahassee, Florida 32306-4295, USA. ; Functional Genomics, Cold Spring Harbor Laboratory, Bungtown Road, Cold Spring Harbor, New York 11724, USA. ; Ludwig Institute for Cancer Research and University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, USA. ; Division of Biology, California Institute of Technology, Pasadena, California 91125, USA. ; 1] Bioinformatics and Genomics, Centre for Genomic Regulation (CRG) and UPF, Doctor Aiguader, 88, 08003 Barcelona, Catalonia, Spain. [2] Department of Theoretical Chemistry, Faculty of Chemistry, University of Vienna, Waehringerstrasse 17/3/303, A-1090 Vienna, Austria. ; Departments of Biology and Mathematics and Computer Science, Emory University, O. Wayne Rollins Research Center, 1510 Clifton Road NE, Atlanta, Georgia 30322, USA. ; 1] Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. [2] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; 1] Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. [2] Department of Radiation Oncology, University of Washington, Seattle, Washington 98195, USA. ; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA. ; 1] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California 92697, USA. ; Center for Biomolecular Science and Engineering, School of Engineering, University of California Santa Cruz (UCSC), Santa Cruz, California 95064, USA. ; Departments of Obstetrics/Gynecology and Pathology, and Center for Reproductive Sciences, University of California San Francisco, San Francisco, California 94143, USA. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; Yale University, Department of Genetics, PO Box 208005, 333 Cedar Street, New Haven, Connecticut 06520-8005, USA. ; Computer &Information Sciences &Engineering, University of Florida, Gainesville, Florida 32611, USA. ; McKusick-Nathans Institute of Genetic Medicine and Department of Biomedical Engineering, Johns Hopkins University, 733 N. Broadway, BRB 573 Baltimore, Maryland 21205, USA. ; 1] European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. [2] Bill Lyons Informatics Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK. ; Department of Biological Structure, University of Washington, HSB I-516, 1959 NE Pacific Street, Seattle, Washington 98195, USA. ; MRC Molecular Haemotology Unit, University of Oxford, Oxford OX3 9DS, UK. ; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA. ; HHMI and Ludwig Center at Memorial Sloan Kettering Cancer Center, Immunology Program, Memorial Sloan Kettering Cancer Canter, New York, New York 10065, USA. ; Dana Farber Cancer Institute, Harvard Medical School, Cambridge, Massachusetts 02138, USA. ; University of Iowa Carver College of Medicine, Department of Internal Medicine, Iowa City, Iowa 52242, USA. ; Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA. ; Department of Pathology, University of Washington, Seattle, Washington 98195, USA. ; Department of Comparative Medicine, University of Washington, Seattle, Washington 98195, USA. ; Bioinformatics and Genomics program, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Department of Hematology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. [2] Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. ; Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108, USA. ; NHGRI, National Institutes of Health, 5635 Fishers Lane, Bethesda, Maryland 20892-9307, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409824" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Lineage/genetics ; Chromatin/genetics/metabolism ; Conserved Sequence/genetics ; DNA Replication/genetics ; Deoxyribonuclease I/metabolism ; Gene Expression Regulation/genetics ; Gene Regulatory Networks/genetics ; Genome/*genetics ; Genome-Wide Association Study ; *Genomics ; Humans ; Mice/*genetics ; *Molecular Sequence Annotation ; RNA/genetics ; Regulatory Sequences, Nucleic Acid/genetics ; Species Specificity ; Transcription Factors/metabolism ; Transcriptome/genetics
    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: 2015-02-20
    Description: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530010/" 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/PMC4530010/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roadmap Epigenomics Consortium -- Kundaje, Anshul -- Meuleman, Wouter -- Ernst, Jason -- Bilenky, Misha -- Yen, Angela -- Heravi-Moussavi, Alireza -- Kheradpour, Pouya -- Zhang, Zhizhuo -- Wang, Jianrong -- Ziller, Michael J -- Amin, Viren -- Whitaker, John W -- Schultz, Matthew D -- Ward, Lucas D -- Sarkar, Abhishek -- Quon, Gerald -- Sandstrom, Richard S -- Eaton, Matthew L -- Wu, Yi-Chieh -- Pfenning, Andreas R -- Wang, Xinchen -- Claussnitzer, Melina -- Liu, Yaping -- Coarfa, Cristian -- Harris, R Alan -- Shoresh, Noam -- Epstein, Charles B -- Gjoneska, Elizabeta -- Leung, Danny -- Xie, Wei -- Hawkins, R David -- Lister, Ryan -- Hong, Chibo -- Gascard, Philippe -- Mungall, Andrew J -- Moore, Richard -- Chuah, Eric -- Tam, Angela -- Canfield, Theresa K -- Hansen, R Scott -- Kaul, Rajinder -- Sabo, Peter J -- Bansal, Mukul S -- Carles, Annaick -- Dixon, Jesse R -- Farh, Kai-How -- Feizi, Soheil -- Karlic, Rosa -- Kim, Ah-Ram -- Kulkarni, Ashwinikumar -- Li, Daofeng -- Lowdon, Rebecca -- Elliott, GiNell -- Mercer, Tim R -- Neph, Shane J -- Onuchic, Vitor -- Polak, Paz -- Rajagopal, Nisha -- Ray, Pradipta -- Sallari, Richard C -- Siebenthall, Kyle T -- Sinnott-Armstrong, Nicholas A -- Stevens, Michael -- Thurman, Robert E -- Wu, Jie -- Zhang, Bo -- Zhou, Xin -- Beaudet, Arthur E -- Boyer, Laurie A -- De Jager, Philip L -- Farnham, Peggy J -- Fisher, Susan J -- Haussler, David -- Jones, Steven J M -- Li, Wei -- Marra, Marco A -- McManus, Michael T -- Sunyaev, Shamil -- Thomson, James A -- Tlsty, Thea D -- Tsai, Li-Huei -- Wang, Wei -- Waterland, Robert A -- Zhang, Michael Q -- Chadwick, Lisa H -- Bernstein, Bradley E -- Costello, Joseph F -- Ecker, Joseph R -- Hirst, Martin -- Meissner, Alexander -- Milosavljevic, Aleksandar -- Ren, Bing -- Stamatoyannopoulos, John A -- Wang, Ting -- Kellis, Manolis -- 5R24HD000836/HD/NICHD NIH HHS/ -- ES017166/ES/NIEHS NIH HHS/ -- F32 HL110473/HL/NHLBI NIH HHS/ -- F32HL110473/HL/NHLBI NIH HHS/ -- K99 HL119617/HL/NHLBI NIH HHS/ -- K99HL119617/HL/NHLBI NIH HHS/ -- P01 DA008227/DA/NIDA NIH HHS/ -- P30AG10161/AG/NIA NIH HHS/ -- P50 MH096890/MH/NIMH NIH HHS/ -- R01 AG015819/AG/NIA NIH HHS/ -- R01 AG017917/AG/NIA NIH HHS/ -- R01 ES024984/ES/NIEHS NIH HHS/ -- R01 ES024992/ES/NIEHS NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- R01 HG007175/HG/NHGRI NIH HHS/ -- R01 HG007354/HG/NHGRI NIH HHS/ -- R01AG15819/AG/NIA NIH HHS/ -- R01AG17917/AG/NIA NIH HHS/ -- R01HG004037/HG/NHGRI NIH HHS/ -- R01HG004037-S1/HG/NHGRI NIH HHS/ -- R01NS078839/NS/NINDS NIH HHS/ -- RC1HG005334/HG/NHGRI NIH HHS/ -- RF1 AG015819/AG/NIA NIH HHS/ -- T32 ES007032/ES/NIEHS NIH HHS/ -- T32 GM007198/GM/NIGMS NIH HHS/ -- T32 GM007266/GM/NIGMS NIH HHS/ -- T32 GM081739/GM/NIGMS NIH HHS/ -- U01 ES017154/ES/NIEHS NIH HHS/ -- U01AG46152/AG/NIA NIH HHS/ -- U01DA025956/DA/NIDA NIH HHS/ -- U01ES017154/ES/NIEHS NIH HHS/ -- U01ES017155/ES/NIEHS NIH HHS/ -- U01ES017156/ES/NIEHS NIH HHS/ -- U01ES017166/ES/NIEHS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Feb 19;518(7539):317-30. doi: 10.1038/nature14248.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, Massachusetts 02139, USA. [2] The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA. [3] Department of Genetics, Department of Computer Science, 300 Pasteur Dr., Lane Building, L301, Stanford, California 94305-5120, USA. ; 1] Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, Massachusetts 02139, USA. [2] The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA. ; 1] Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, Massachusetts 02139, USA. [2] The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA. [3] Department of Biological Chemistry, University of California, Los Angeles, 615 Charles E Young Dr South, Los Angeles, California 90095, USA. ; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada. ; 1] The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA. [2] Department of Stem Cell and Regenerative Biology, 7 Divinity Ave, Cambridge, Massachusetts 02138, USA. ; Epigenome Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. ; Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, Moores Cancer Center, Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. ; Genomic Analysis Laboratory, Howard Hughes Medical Institute &The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, California 92037, USA. ; Department of Genome Sciences, University of Washington, 3720 15th Ave. NE, Seattle, Washington 98195, USA. ; 1] Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, Massachusetts 02139, USA. [2] The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA. [3] Biology Department, Massachusetts Institute of Technology, 31 Ames St, Cambridge, Massachusetts 02142, USA. ; The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA. ; 1] The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA. [2] The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 43 Vassar St, Cambridge, Massachusetts 02139, USA. ; 1] Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, Moores Cancer Center, Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. [2] Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, California 92093, USA. ; Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1450 3rd Street, San Francisco, California 94158, USA. ; Department of Pathology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, California 94143-0511, USA. ; Department of Medicine, Division of Medical Genetics, University of Washington, 2211 Elliot Avenue, Seattle, Washington 98121, USA. ; 1] Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, Massachusetts 02139, USA. [2] The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA. [3] Department of Computer Science &Engineering, University of Connecticut, 371 Fairfield Way, Storrs, Connecticut 06269, USA. ; Department of Microbiology and Immunology and Centre for High-Throughput Biology, University of British Columbia, 2125 East Mall, Vancouver, British Columbia V6T 1Z4, Canada. ; Bioinformatics Group, Department of Molecular Biology, Division of Biology, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia. ; Department of Molecular and Cell Biology, Center for Systems Biology, The University of Texas, Dallas, NSERL, RL10, 800 W Campbell Road, Richardson, Texas 75080, USA. ; Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University in St Louis, 4444 Forest Park Ave, St Louis, Missouri 63108, USA. ; Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia. ; 1] The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA. [2] Brigham &Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA. ; 1] Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University in St Louis, 4444 Forest Park Ave, St Louis, Missouri 63108, USA. [2] Department of Computer Science and Engineeering, Washington University in St. Louis, St. Louis, Missouri 63130, USA. ; 1] Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York 11794-3600, USA. [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; Molecular and Human Genetics Department, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. ; Biology Department, Massachusetts Institute of Technology, 31 Ames St, Cambridge, Massachusetts 02142, USA. ; 1] The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA. [2] Brigham &Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA. [3] Harvard Medical School, 25 Shattuck St, Boston, Massachusetts 02115, USA. ; Department of Biochemistry, Keck School of Medicine, University of Southern California, 1450 Biggy Street, Los Angeles, California 90089-9601, USA. ; ObGyn, Reproductive Sciences, University of California San Francisco, 35 Medical Center Way, San Francisco, California 94143, USA. ; Center for Biomolecular Sciences and Engineering, University of Santa Cruz, 1156 High Street, Santa Cruz, California 95064, USA. ; 1] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada. [2] Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada. [3] Department of Medical Genetics, University of British Columbia, 2329 West Mall, Vancouver, BC, Canada, V6T 1Z4. ; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. ; 1] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada. [2] Department of Medical Genetics, University of British Columbia, 2329 West Mall, Vancouver, BC, Canada, V6T 1Z4. ; Department of Microbiology and Immunology, Diabetes Center, University of California, San Francisco, 513 Parnassus Ave, San Francisco, California 94143-0534, USA. ; 1] University of Wisconsin, Madison, Wisconsin 53715, USA. [2] Morgridge Institute for Research, 330 N. Orchard Street, Madison, Wisconsin 53707, USA. ; USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, 1100 Bates Street, Houston, Texas 77030, USA. ; 1] Department of Molecular and Cell Biology, Center for Systems Biology, The University of Texas, Dallas, NSERL, RL10, 800 W Campbell Road, Richardson, Texas 75080, USA. [2] Bioinformatics Division, Center for Synthetic and Systems Biology, TNLIST, Tsinghua University, Beijing 100084, China. ; National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, Research Triangle Park, North Carolina 27709, USA. ; 1] The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA. [2] Massachusetts General Hospital, 55 Fruit St, Boston, Massachusetts 02114, USA. [3] Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815-6789, USA. ; 1] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada. [2] Department of Microbiology and Immunology and Centre for High-Throughput Biology, University of British Columbia, 2125 East Mall, Vancouver, British Columbia V6T 1Z4, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25693563" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Cell Lineage/genetics ; Cells, Cultured ; Chromatin/chemistry/genetics/metabolism ; Chromosomes, Human/chemistry/genetics/metabolism ; DNA/chemistry/genetics/metabolism ; DNA Methylation ; Datasets as Topic ; Enhancer Elements, Genetic/genetics ; Epigenesis, Genetic/*genetics ; *Epigenomics ; Genetic Variation/genetics ; Genome, Human/*genetics ; Genome-Wide Association Study ; Histones/metabolism ; Humans ; Organ Specificity/genetics ; RNA/genetics ; Reference Values
    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: 2014-11-21
    Description: Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program. In mammals, replication timing is cell-type-specific with at least half the genome switching replication timing during development, primarily in units of 400-800 kilobases ('replication domains'), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs). Recent Hi-C mapping has unveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replication domain boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type-specific replication timing of TADs partitions the genome into two large-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timing with developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251741/" 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/PMC4251741/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pope, Benjamin D -- Ryba, Tyrone -- Dileep, Vishnu -- Yue, Feng -- Wu, Weisheng -- Denas, Olgert -- Vera, Daniel L -- Wang, Yanli -- Hansen, R Scott -- Canfield, Theresa K -- Thurman, Robert E -- Cheng, Yong -- Gulsoy, Gunhan -- Dennis, Jonathan H -- Snyder, Michael P -- Stamatoyannopoulos, John A -- Taylor, James -- Hardison, Ross C -- Kahveci, Tamer -- Ren, Bing -- Gilbert, David M -- DK065806/DK/NIDDK NIH HHS/ -- F31 CA165863/CA/NCI NIH HHS/ -- F31CA165863/CA/NCI NIH HHS/ -- GM083337/GM/NIGMS NIH HHS/ -- GM085354/GM/NIGMS NIH HHS/ -- HG003991/HG/NHGRI NIH HHS/ -- HG005573/HG/NHGRI NIH HHS/ -- HG005602/HG/NHGRI NIH HHS/ -- P01 GM085354/GM/NIGMS NIH HHS/ -- R01 DA033775/DA/NIDA NIH HHS/ -- R01 DK065806/DK/NIDDK NIH HHS/ -- R01 GM083337/GM/NIGMS NIH HHS/ -- R56 DK065806/DK/NIDDK NIH HHS/ -- RC2 HG005573/HG/NHGRI NIH HHS/ -- U54 HG006997/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Nov 20;515(7527):402-5. doi: 10.1038/nature13986.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Science, 319 Stadium Drive, Florida State University, Tallahassee, Florida 32306, USA. ; Division of Natural Sciences, 5800 Bay Shore Road, New College of Florida, Sarasota, Florida 34243, USA. ; 1] Department of Biochemistry and Molecular Biology, School of Medicine, The Pennsylvania State University, Hershey, Pennsylvania 17033, USA [2] Bioinformatics and Genomics Program, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Center for Comparative Genomics and Bioinformatics, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Departments of Biology and Mathematics and Computer Science, Emory University, O. Wayne Rollins Research Center, 1510 Clifton Road NE, Atlanta, Georgia 30322, USA. ; Bioinformatics and Genomics Program, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA. ; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. ; Department of Genetics, Stanford University, 300 Pasteur Drive, MC-5477 Stanford, California 94305, USA. ; Computer and Information Sciences and Engineering, University of Florida, Gainesville, Florida 32611, USA. ; Ludwig Institute for Cancer Research and University of California, San Diego School of Medicine, 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/25409831" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Compartmentation ; Chromatin/*chemistry/*genetics/metabolism ; Chromatin Assembly and Disassembly ; DNA/*biosynthesis/genetics ; *DNA Replication Timing ; Genome/genetics ; Heterochromatin/chemistry/genetics/metabolism ; Humans ; Mice ; Organ Specificity ; Time Factors
    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: 2012-09-08
    Description: Genome-wide association studies have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs). Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure-related phenotypes. We identified distant gene targets for hundreds of variant-containing DHSs that may explain phenotype associations. Disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks. We also demonstrated tissue-selective enrichment of more weakly disease-associated variants within DHSs and the de novo identification of pathogenic cell types for Crohn's disease, multiple sclerosis, and an electrocardiogram trait, without prior knowledge of physiological mechanisms. Our results suggest pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771521/" 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/PMC3771521/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maurano, Matthew T -- Humbert, Richard -- Rynes, Eric -- Thurman, Robert E -- Haugen, Eric -- Wang, Hao -- Reynolds, Alex P -- Sandstrom, Richard -- Qu, Hongzhu -- Brody, Jennifer -- Shafer, Anthony -- Neri, Fidencio -- Lee, Kristen -- Kutyavin, Tanya -- Stehling-Sun, Sandra -- Johnson, Audra K -- Canfield, Theresa K -- Giste, Erika -- Diegel, Morgan -- Bates, Daniel -- Hansen, R Scott -- Neph, Shane -- Sabo, Peter J -- Heimfeld, Shelly -- Raubitschek, Antony -- Ziegler, Steven -- Cotsapas, Chris -- Sotoodehnia, Nona -- Glass, Ian -- Sunyaev, Shamil R -- Kaul, Rajinder -- Stamatoyannopoulos, John A -- F31 MH094073/MH/NIMH NIH HHS/ -- P30 DK056465/DK/NIDDK NIH HHS/ -- R01 HL088456/HL/NHLBI NIH HHS/ -- R01HL088456/HL/NHLBI NIH HHS/ -- R24 HD000836/HD/NICHD NIH HHS/ -- R24HD000836-47/HD/NICHD NIH HHS/ -- U01ES01156/ES/NIEHS NIH HHS/ -- U54 HG004592/HG/NHGRI NIH HHS/ -- U54HG004592/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2012 Sep 7;337(6099):1190-5. doi: 10.1126/science.1222794. Epub 2012 Sep 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22955828" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Chromatin/metabolism/ultrastructure ; Crohn Disease/genetics ; DNA/*genetics ; Deoxyribonuclease I/metabolism ; Disease/*genetics ; Electrocardiography ; Fetal Development ; Fetus/metabolism ; Gene Regulatory Networks ; *Genetic Variation ; Genome, Human ; Genome-Wide Association Study ; Humans ; Multiple Sclerosis/genetics ; Phenotype ; *Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; *Regulatory Elements, Transcriptional ; *Regulatory Sequences, Nucleic Acid ; Transcription Factors/chemistry/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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  • 7
    Publication Date: 2012-09-08
    Description: DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify approximately 2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect approximately 580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721348/" 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/PMC3721348/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thurman, Robert E -- Rynes, Eric -- Humbert, Richard -- Vierstra, Jeff -- Maurano, Matthew T -- Haugen, Eric -- Sheffield, Nathan C -- Stergachis, Andrew B -- Wang, Hao -- Vernot, Benjamin -- Garg, Kavita -- John, Sam -- Sandstrom, Richard -- Bates, Daniel -- Boatman, Lisa -- Canfield, Theresa K -- Diegel, Morgan -- Dunn, Douglas -- Ebersol, Abigail K -- Frum, Tristan -- Giste, Erika -- Johnson, Audra K -- Johnson, Ericka M -- Kutyavin, Tanya -- Lajoie, Bryan -- Lee, Bum-Kyu -- Lee, Kristen -- London, Darin -- Lotakis, Dimitra -- Neph, Shane -- Neri, Fidencio -- Nguyen, Eric D -- Qu, Hongzhu -- Reynolds, Alex P -- Roach, Vaughn -- Safi, Alexias -- Sanchez, Minerva E -- Sanyal, Amartya -- Shafer, Anthony -- Simon, Jeremy M -- Song, Lingyun -- Vong, Shinny -- Weaver, Molly -- Yan, Yongqi -- Zhang, Zhancheng -- Zhang, Zhuzhu -- Lenhard, Boris -- Tewari, Muneesh -- Dorschner, Michael O -- Hansen, R Scott -- Navas, Patrick A -- Stamatoyannopoulos, George -- Iyer, Vishwanath R -- Lieb, Jason D -- Sunyaev, Shamil R -- Akey, Joshua M -- Sabo, Peter J -- Kaul, Rajinder -- Furey, Terrence S -- Dekker, Job -- Crawford, Gregory E -- Stamatoyannopoulos, John A -- F30 DK095678/DK/NIDDK NIH HHS/ -- GM076036/GM/NIGMS NIH HHS/ -- HG004563/HG/NHGRI NIH HHS/ -- HG004592/HG/NHGRI NIH HHS/ -- HHSN261200800001E/PHS HHS/ -- MC_UP_1102/1/Medical Research Council/United Kingdom -- P30 CA016086/CA/NCI NIH HHS/ -- R01 GM076036/GM/NIGMS NIH HHS/ -- R01 HG003143/HG/NHGRI NIH HHS/ -- R01 MH084676/MH/NIMH NIH HHS/ -- R01MH084676/MH/NIMH NIH HHS/ -- U54 HG004563/HG/NHGRI NIH HHS/ -- U54 HG004592/HG/NHGRI NIH HHS/ -- England -- Nature. 2012 Sep 6;489(7414):75-82. doi: 10.1038/nature11232.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22955617" target="_blank"〉PubMed〈/a〉
    Keywords: Chromatin/*genetics/*metabolism ; DNA/*genetics ; DNA Footprinting ; DNA Methylation ; DNA-Binding Proteins/metabolism ; Deoxyribonuclease I/metabolism ; *Encyclopedias as Topic ; Evolution, Molecular ; Genome, Human/*genetics ; Genomics ; Humans ; *Molecular Sequence Annotation ; Mutation Rate ; Promoter Regions, Genetic/genetics ; Regulatory Sequences, Nucleic Acid/*genetics ; Transcription Factors/metabolism ; Transcription Initiation Site ; Transcription, Genetic
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2012-09-08
    Description: Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNase I, leaving nucleotide-resolution footprints. Using genomic DNase I footprinting across 41 diverse cell and tissue types, we detected 45 million transcription factor occupancy events within regulatory regions, representing differential binding to 8.4 million distinct short sequence elements. Here we show that this small genomic sequence compartment, roughly twice the size of the exome, encodes an expansive repertoire of conserved recognition sequences for DNA-binding proteins that nearly doubles the size of the human cis-regulatory lexicon. We find that genetic variants affecting allelic chromatin states are concentrated in footprints, and that these elements are preferentially sheltered from DNA methylation. High-resolution DNase I cleavage patterns mirror nucleotide-level evolutionary conservation and track the crystallographic topography of protein-DNA interfaces, indicating that transcription factor structure has been evolutionarily imprinted on the human genome sequence. We identify a stereotyped 50-base-pair footprint that precisely defines the site of transcript origination within thousands of human promoters. Finally, we describe a large collection of novel regulatory factor recognition motifs that are highly conserved in both sequence and function, and exhibit cell-selective occupancy patterns that closely parallel major regulators of development, differentiation and pluripotency.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736582/" 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/PMC3736582/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Neph, Shane -- Vierstra, Jeff -- Stergachis, Andrew B -- Reynolds, Alex P -- Haugen, Eric -- Vernot, Benjamin -- Thurman, Robert E -- John, Sam -- Sandstrom, Richard -- Johnson, Audra K -- Maurano, Matthew T -- Humbert, Richard -- Rynes, Eric -- Wang, Hao -- Vong, Shinny -- Lee, Kristen -- Bates, Daniel -- Diegel, Morgan -- Roach, Vaughn -- Dunn, Douglas -- Neri, Jun -- Schafer, Anthony -- Hansen, R Scott -- Kutyavin, Tanya -- Giste, Erika -- Weaver, Molly -- Canfield, Theresa -- Sabo, Peter -- Zhang, Miaohua -- Balasundaram, Gayathri -- Byron, Rachel -- MacCoss, Michael J -- Akey, Joshua M -- Bender, M A -- Groudine, Mark -- Kaul, Rajinder -- Stamatoyannopoulos, John A -- F30 DK095678/DK/NIDDK NIH HHS/ -- HG004592/HG/NHGRI NIH HHS/ -- P30 CA015704/CA/NCI NIH HHS/ -- R37 DK044746/DK/NIDDK NIH HHS/ -- RC2 HG005654/HG/NHGRI NIH HHS/ -- RC2HG005654/HG/NHGRI NIH HHS/ -- U54 HG004592/HG/NHGRI NIH HHS/ -- England -- Nature. 2012 Sep 6;489(7414):83-90. doi: 10.1038/nature11212.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22955618" target="_blank"〉PubMed〈/a〉
    Keywords: DNA/*genetics ; *DNA Footprinting ; DNA Methylation ; DNA-Binding Proteins/metabolism ; Deoxyribonuclease I/metabolism ; *Encyclopedias as Topic ; Genome, Human/*genetics ; Genomic Imprinting ; Genomics ; Humans ; *Molecular Sequence Annotation ; Polymorphism, Single Nucleotide/genetics ; Regulatory Sequences, Nucleic Acid/*genetics ; Transcription Factors/*metabolism ; Transcription Initiation Site
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2014-11-21
    Description: To study the evolutionary dynamics of regulatory DNA, we mapped 〉1.3 million deoxyribonuclease I-hypersensitive sites (DHSs) in 45 mouse cell and tissue types, and systematically compared these with human DHS maps from orthologous compartments. We found that the mouse and human genomes have undergone extensive cis-regulatory rewiring that combines branch-specific evolutionary innovation and loss with widespread repurposing of conserved DHSs to alternative cell fates, and that this process is mediated by turnover of transcription factor (TF) recognition elements. Despite pervasive evolutionary remodeling of the location and content of individual cis-regulatory regions, within orthologous mouse and human cell types the global fraction of regulatory DNA bases encoding recognition sites for each TF has been strictly conserved. Our findings provide new insights into the evolutionary forces shaping mammalian regulatory DNA landscapes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337786/" 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/PMC4337786/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vierstra, Jeff -- Rynes, Eric -- Sandstrom, Richard -- Zhang, Miaohua -- Canfield, Theresa -- Hansen, R Scott -- Stehling-Sun, Sandra -- Sabo, Peter J -- Byron, Rachel -- Humbert, Richard -- Thurman, Robert E -- Johnson, Audra K -- Vong, Shinny -- Lee, Kristen -- Bates, Daniel -- Neri, Fidencio -- Diegel, Morgan -- Giste, Erika -- Haugen, Eric -- Dunn, Douglas -- Wilken, Matthew S -- Josefowicz, Steven -- Samstein, Robert -- Chang, Kai-Hsin -- Eichler, Evan E -- De Bruijn, Marella -- Reh, Thomas A -- Skoultchi, Arthur -- Rudensky, Alexander -- Orkin, Stuart H -- Papayannopoulou, Thalia -- Treuting, Piper M -- Selleri, Licia -- Kaul, Rajinder -- Groudine, Mark -- Bender, M A -- Stamatoyannopoulos, John A -- 1RC2HG005654/HG/NHGRI NIH HHS/ -- 2R01HD04399709/HD/NICHD NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- R01 DK096266/DK/NIDDK NIH HHS/ -- R01 EY021482/EY/NEI NIH HHS/ -- R01 HD043997/HD/NICHD NIH HHS/ -- R37 DK044746/DK/NIDDK NIH HHS/ -- R37DK44746/DK/NIDDK NIH HHS/ -- RC2 HG005654/HG/NHGRI NIH HHS/ -- U54 HG007010/HG/NHGRI NIH HHS/ -- U54HG007010/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Nov 21;346(6212):1007-12. doi: 10.1126/science.1246426.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. ; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. ; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA. ; Department of Biological Structure, University of Washington, Seattle, WA 98195, USA. ; Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Howard Hughes Medical Institute. ; Division of Hematology, Department of Medicine, University of Washington, Seattle, WA 98195, USA. ; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Howard Hughes Medical Institute. ; Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK. ; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. ; Howard Hughes Medical Institute. Division of Hematology/Oncology, Children's Hospital Boston and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA. ; Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA. ; Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY 10065, USA. ; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA. ; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Radiation Oncology, University of Washington, Seattle, WA 98109, USA. ; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. ; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Division of Oncology, Department of Medicine, University of Washington, Seattle, WA 98195, USA. jstam@uw.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25411453" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; *Conserved Sequence ; DNA/*genetics ; Deoxyribonuclease I ; *Evolution, Molecular ; Genome, Human ; Humans ; Mice ; Regulatory Sequences, Nucleic Acid/*genetics ; Restriction Mapping ; Transcription Factors/*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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  • 10
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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