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Nature. 2015 Feb 19;518(7539):317-30. doi: 10.1038/nature14248.

Integrative analysis of 111 reference human epigenomes.

Collaborators (258)

Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, Ziller MJ, Amin V, Whitaker JW, Schultz MD, Ward LD, Sarkar A, Quon G, Sandstrom RS, Eaton ML, Wu YC, Pfenning A, Wang X, Claussnitzer M, Liu Y, Coarfa C, Harris RA, Shoresh N, Epstein CB, Gjoneska E, Leung D, Xie W, Hawkins RD, Lister R, Hong C, Gascard P, Mungall AJ, Moore R, Chuah E, Tam A, Canfield TK, Hansen RS, Kaul R, Sabo PJ, Bansal MS, Carles A, Dixon JR, Farh KH, Feizi S, Karlic R, Kim AR, Kulkarni A, Li D, Lowdon R, Elliott G, Mercer TR, Neph SJ, Onuchic V, Polak P, Rajagopal N, Ray P, Sallari RC, Siebenthall KT, Sinnott-Armstrong NA, Stevens M, Thurman RE, Wu J, Zhang B, Zhou X, Abdennur N, Adli M, Akerman M, Barrera L, Antosiewicz-Bourget J, Ballinger T, Barnes MJ, Bates D, Bell RJ, Bennett DA, Bianco K, Bock C, Boyle P, Brinchmann J, Caballero-Campo P, Camahort R, Carrasco-Alfonso MJ, Charnecki T, Chen H, Chen Z, Cheng JB, Cho S, Chu A, Chung WY, Cowan C, Athena Deng Q, Deshpande V, Diegel M, Ding B, Durham T, Echipare L, Edsall L, Flowers D, Genbacev-Krtolica O, Gifford C, Gillespie S, Giste E, Glass IA, Gnirke A, Gormley M, Gu H, Gu J, Hafler DA, Hangauer MJ, Hariharan M, Hatan M, Haugen E, He Y, Heimfeld S, Herlofsen S, Hou Z, Humbert R, Issner R, Jackson AR, Jia H, Jiang P, Johnson AK, Kadlecek T, Kamoh B, Kapidzic M, Kent J, Kim A, Kleinewietfeld M, Klugman S, Krishnan J, Kuan S, Kutyavin T, Lee AY, Lee K, Li J, Li N, Li Y, Ligon KL, Lin S, Lin Y, Liu J, Liu Y, Luckey CJ, Ma YP, Maire C, Marson A, Mattick JS, Mayo M, McMaster M, Metsky H, Mikkelsen T, Miller D, Miri M, Mukamel E, Nagarajan RP, Neri F, Nery J, Nguyen T, O'Geen H, Paithankar S, Papayannopoulou T, Pelizzola M, Plettner P, Propson NE, Raghuraman S, Raney BJ, Raubitschek A, Reynolds AP, Richards H, Riehle K, Rinaudo P, Robinson JF, Rockweiler NB, Rosen E, Rynes E, Schein J, Sears R, Sejnowski T, Shafer A, Shen L, Shoemaker R, Sigaroudinia M, Slukvin I, Stehling-Sun S, Stewart R, Subramanian SL, Suknuntha K, Swanson S, Tian S, Tilden H, Tsai L, Urich M, Vaughn I, Vierstra J, Vong S, Wagner U, Wang H, Wang T, Wang Y, Weiss A, Whitton H, Wildberg A, Witt H, Won KJ, Xie M, Xing X, Xu I, Xuan Z, Ye Z, Yen CA, Yu P, Zhang X, Zhang X, Zhao J, Zhou Y, Zhu J, Zhu Y, Ziegler S, Beaudet AE, Boyer LA, De Jager PL, Farnham PJ, Fisher SJ, Haussler D, Jones SJ, Li W, Marra MA, McManus MT, Sunyaev S, Thomson JA, Tlsty TD, Tsai LH, Wang W, Waterland RA, Zhang MQ, Chadwick LH, Bernstein BE, Costello JF, Ecker JR, Hirst M, Meissner A, Milosavljevic A, Ren B, Stamatoyannopoulos JA, Wang T, Kellis M, Bernstein BE, Costello JF, Ecker JR, Hirst M, Meissner A, Milosavljevic A, Ren B, Stamatoyannopoulos JA, Wang T, Kellis M.

Author information

1
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.
2
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
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.
4
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
5
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.
6
Epigenome Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
7
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.
8
Genomic Analysis Laboratory, Howard Hughes Medical Institute &The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, California 92037, USA.
9
Department of Genome Sciences, University of Washington, 3720 15th Ave. NE, Seattle, Washington 98195, USA.
10
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.
11
The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
12
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.
13
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.
14
Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1450 3rd Street, San Francisco, California 94158, USA.
15
Department of Pathology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, California 94143-0511, USA.
16
Department of Medicine, Division of Medical Genetics, University of Washington, 2211 Elliot Avenue, Seattle, Washington 98121, USA.
17
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.
18
Department of Microbiology and Immunology and Centre for High-Throughput Biology, University of British Columbia, 2125 East Mall, Vancouver, British Columbia V6T 1Z4, Canada.
19
Bioinformatics Group, Department of Molecular Biology, Division of Biology, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia.
20
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.
21
Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University in St Louis, 4444 Forest Park Ave, St Louis, Missouri 63108, USA.
22
Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia.
23
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.
24
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.
25
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.
26
Molecular and Human Genetics Department, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
27
Biology Department, Massachusetts Institute of Technology, 31 Ames St, Cambridge, Massachusetts 02142, USA.
28
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.
29
Department of Biochemistry, Keck School of Medicine, University of Southern California, 1450 Biggy Street, Los Angeles, California 90089-9601, USA.
30
ObGyn, Reproductive Sciences, University of California San Francisco, 35 Medical Center Way, San Francisco, California 94143, USA.
31
Center for Biomolecular Sciences and Engineering, University of Santa Cruz, 1156 High Street, Santa Cruz, California 95064, USA.
32
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.
33
Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
34
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.
35
Department of Microbiology and Immunology, Diabetes Center, University of California, San Francisco, 513 Parnassus Ave, San Francisco, California 94143-0534, USA.
36
1] University of Wisconsin, Madison, Wisconsin 53715, USA. [2] Morgridge Institute for Research, 330 N. Orchard Street, Madison, Wisconsin 53707, USA.
37
USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, 1100 Bates Street, Houston, Texas 77030, USA.
38
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.
39
National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, Research Triangle Park, North Carolina 27709, USA.
40
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.
41
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.

Abstract

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.

PMID:
25693563
PMCID:
PMC4530010
DOI:
10.1038/nature14248
[Indexed for MEDLINE]
Free PMC Article

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