Index and biological spectrum of human DNase I hypersensitive sites

Wouter Meuleman (), Alexander Muratov, Eric Rynes, Jessica Halow, Kristen Lee, Daniel Bates, Morgan Diegel, Douglas Dunn, Fidencio Neri, Athanasios Teodosiadis, Alex Reynolds, Eric Haugen, Jemma Nelson, Audra Johnson, Mark Frerker, Michael Buckley, Richard Sandstrom, Jeff Vierstra, Rajinder Kaul and John Stamatoyannopoulos ()
Additional contact information
Wouter Meuleman: Altius Institute for Biomedical Sciences
Alexander Muratov: Altius Institute for Biomedical Sciences
Eric Rynes: Altius Institute for Biomedical Sciences
Jessica Halow: Altius Institute for Biomedical Sciences
Kristen Lee: Altius Institute for Biomedical Sciences
Daniel Bates: Altius Institute for Biomedical Sciences
Morgan Diegel: Altius Institute for Biomedical Sciences
Douglas Dunn: Altius Institute for Biomedical Sciences
Fidencio Neri: Altius Institute for Biomedical Sciences
Athanasios Teodosiadis: Altius Institute for Biomedical Sciences
Alex Reynolds: Altius Institute for Biomedical Sciences
Eric Haugen: Altius Institute for Biomedical Sciences
Jemma Nelson: Altius Institute for Biomedical Sciences
Audra Johnson: Altius Institute for Biomedical Sciences
Mark Frerker: Altius Institute for Biomedical Sciences
Michael Buckley: Altius Institute for Biomedical Sciences
Richard Sandstrom: Altius Institute for Biomedical Sciences
Jeff Vierstra: Altius Institute for Biomedical Sciences
Rajinder Kaul: Altius Institute for Biomedical Sciences
John Stamatoyannopoulos: Altius Institute for Biomedical Sciences

Nature, 2020, vol. 584, issue 7820, 244-251

Abstract: Abstract DNase I hypersensitive sites (DHSs) are generic markers of regulatory DNA1–5 and contain genetic variations associated with diseases and phenotypic traits6–8. We created high-resolution maps of DHSs from 733 human biosamples encompassing 438 cell and tissue types and states, and integrated these to delineate and numerically index approximately 3.6 million DHSs within the human genome sequence, providing a common coordinate system for regulatory DNA. Here we show that these maps highly resolve the cis-regulatory compartment of the human genome, which encodes unexpectedly diverse cell- and tissue-selective regulatory programs at very high density. These programs can be captured comprehensively by a simple vocabulary that enables the assignment to each DHS of a regulatory barcode that encapsulates its tissue manifestations, and global annotation of protein-coding and non-coding RNA genes in a manner orthogonal to gene expression. Finally, we show that sharply resolved DHSs markedly enhance the genetic association and heritability signals of diseases and traits. Rather than being confined to a small number of distal elements or promoters, we find that genetic signals converge on congruently regulated sets of DHSs that decorate entire gene bodies. Together, our results create a universal, extensible coordinate system and vocabulary for human regulatory DNA marked by DHSs, and provide a new global perspective on the architecture of human gene regulation.

Date: 2020
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DOI: 10.1038/s41586-020-2559-3

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