The accessible chromatin landscape of the human genome

Robert E. Thurman, Eric Rynes, Richard Humbert, Jeff Vierstra, Matthew T. Maurano, Eric Haugen, Nathan C. Sheffield, Andrew B. Stergachis, Hao Wang, Benjamin Vernot, Kavita Garg, Sam John, Richard Sandstrom, Daniel Bates, Lisa Boatman, Theresa K. Canfield, Morgan Diegel, Douglas Dunn, Abigail K. Ebersol, Tristan Frum, Erika Giste, Audra K. Johnson, Ericka M. Johnson, Tanya Kutyavin, Bryan Lajoie, Bum-Kyu Lee, Kristen Lee, Darin London, Dimitra Lotakis, Shane Neph, Fidencio Neri, Eric D. Nguyen, Hongzhu Qu, Alex P. Reynolds, Vaughn Roach, Alexias Safi, Minerva E. Sanchez, Amartya Sanyal, Anthony Shafer, Jeremy M. Simon, Lingyun Song, Shinny Vong, Molly Weaver, Yongqi Yan, Zhancheng Zhang, Zhuzhu Zhang, Boris Lenhard, Muneesh Tewari, Michael O. Dorschner, R. Scott Hansen, Patrick A. Navas, George Stamatoyannopoulos, Vishwanath R. Iyer, Jason D. Lieb, Shamil R. Sunyaev, Joshua M. Akey, Peter J. Sabo, Rajinder Kaul, Terrence S. Furey, Job Dekker, Gregory E. Crawford and John A. Stamatoyannopoulos ()
Additional contact information
Robert E. Thurman: University of Washington
Eric Rynes: University of Washington
Richard Humbert: University of Washington
Jeff Vierstra: University of Washington
Matthew T. Maurano: University of Washington
Eric Haugen: University of Washington
Nathan C. Sheffield: Institute for Genome Sciences and Policy, Duke University
Andrew B. Stergachis: University of Washington
Hao Wang: University of Washington
Benjamin Vernot: University of Washington
Kavita Garg: Fred Hutchinson Cancer Research Center
Sam John: University of Washington
Richard Sandstrom: University of Washington
Daniel Bates: University of Washington
Lisa Boatman: University of Washington
Theresa K. Canfield: University of Washington
Morgan Diegel: University of Washington
Douglas Dunn: University of Washington
Abigail K. Ebersol: University of Washington
Tristan Frum: University of Washington
Erika Giste: University of Washington
Audra K. Johnson: University of Washington
Ericka M. Johnson: University of Washington
Tanya Kutyavin: University of Washington
Bryan Lajoie: Program in Systems Biology, University of Massachusetts Medical School
Bum-Kyu Lee: Institute for Cellular and Molecular Biology, University of Texas
Kristen Lee: University of Washington
Darin London: Institute for Genome Sciences and Policy, Duke University
Dimitra Lotakis: University of Washington
Shane Neph: University of Washington
Fidencio Neri: University of Washington
Eric D. Nguyen: University of Washington
Hongzhu Qu: University of Washington
Alex P. Reynolds: University of Washington
Vaughn Roach: University of Washington
Alexias Safi: Institute for Genome Sciences and Policy, Duke University
Minerva E. Sanchez: University of Washington
Amartya Sanyal: Program in Systems Biology, University of Massachusetts Medical School
Anthony Shafer: University of Washington
Jeremy M. Simon: University of North Carolina
Lingyun Song: Institute for Genome Sciences and Policy, Duke University
Shinny Vong: University of Washington
Molly Weaver: University of Washington
Yongqi Yan: University of Washington
Zhancheng Zhang: University of North Carolina
Zhuzhu Zhang: University of North Carolina
Boris Lenhard: University of Bergen, Bergen 5008, Norway
Muneesh Tewari: Fred Hutchinson Cancer Research Center
Michael O. Dorschner: University of Washington
R. Scott Hansen: University of Washington
Patrick A. Navas: University of Washington
George Stamatoyannopoulos: University of Washington
Vishwanath R. Iyer: Institute for Cellular and Molecular Biology, University of Texas
Jason D. Lieb: University of North Carolina
Shamil R. Sunyaev: Brigham & Women’s Hospital and Harvard Medical School
Joshua M. Akey: University of Washington
Peter J. Sabo: University of Washington
Rajinder Kaul: University of Washington
Terrence S. Furey: University of North Carolina
Job Dekker: Program in Systems Biology, University of Massachusetts Medical School
Gregory E. Crawford: Institute for Genome Sciences and Policy, Duke University
John A. Stamatoyannopoulos: University of Washington

Nature, 2012, vol. 489, issue 7414, 75-82

Abstract: Abstract 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 ∼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 ∼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.

Date: 2012
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DOI: 10.1038/nature11232

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