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Index and biological spectrum of human DNase I hypersensitive sites

Author

Listed:
  • 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
    University of Washington
    University of Washington)

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.

Suggested Citation

  • Wouter Meuleman & Alexander Muratov & Eric Rynes & Jessica Halow & Kristen Lee & Daniel Bates & Morgan Diegel & Douglas Dunn & Fidencio Neri & Athanasios Teodosiadis & Alex Reynolds & Eric Haugen & Je, 2020. "Index and biological spectrum of human DNase I hypersensitive sites," Nature, Nature, vol. 584(7820), pages 244-251, August.
  • Handle: RePEc:nat:nature:v:584:y:2020:i:7820:d:10.1038_s41586-020-2559-3
    DOI: 10.1038/s41586-020-2559-3
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    1. Denis Houzelstein & Caroline Eozenou & Carlos F. Lagos & Maëva Elzaiat & Joelle Bignon-Topalovic & Inma Gonzalez & Vincent Laville & Laurène Schlick & Somboon Wankanit & Prochi Madon & Jyotsna Kirtane, 2024. "A conserved NR5A1-responsive enhancer regulates SRY in testis-determination," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Milton Pividori & Sumei Lu & Binglan Li & Chun Su & Matthew E. Johnson & Wei-Qi Wei & Qiping Feng & Bahram Namjou & Krzysztof Kiryluk & Iftikhar J. Kullo & Yuan Luo & Blair D. Sullivan & Benjamin F. V, 2023. "Projecting genetic associations through gene expression patterns highlights disease etiology and drug mechanisms," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Ingrid M. Saldana-Guerrero & Luis F. Montano-Gutierrez & Katy Boswell & Christoph Hafemeister & Evon Poon & Lisa E. Shaw & Dylan Stavish & Rebecca A. Lea & Sara Wernig-Zorc & Eva Bozsaky & Irfete S. F, 2024. "A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    4. Anna-Lisa Doebley & Minjeong Ko & Hanna Liao & A. Eden Cruikshank & Katheryn Santos & Caroline Kikawa & Joseph B. Hiatt & Robert D. Patton & Navonil De Sarkar & Katharine A. Collier & Anna C. H. Hoge , 2022. "A framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    5. Kaela M. Varberg & Esteban M. Dominguez & Boryana Koseva & Joseph M. Varberg & Ross P. McNally & Ayelen Moreno-Irusta & Emily R. Wesley & Khursheed Iqbal & Warren A. Cheung & Carl Schwendinger-Schreck, 2023. "Extravillous trophoblast cell lineage development is associated with active remodeling of the chromatin landscape," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    6. Lucia Trastulla & Georgii Dolgalev & Sylvain Moser & Laura T. Jiménez-Barrón & Till F. M. Andlauer & Moritz Scheidt & Monika Budde & Urs Heilbronner & Sergi Papiol & Alexander Teumer & Georg Homuth & , 2024. "Distinct genetic liability profiles define clinically relevant patient strata across common diseases," Nature Communications, Nature, vol. 15(1), pages 1-28, December.
    7. Hillary Koch & Cheryl A. Keller & Guanjue Xiang & Belinda Giardine & Feipeng Zhang & Yicheng Wang & Ross C. Hardison & Qunhua Li, 2022. "CLIMB: High-dimensional association detection in large scale genomic data," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Chirag Nepal & Jesper B. Andersen, 2023. "Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    9. Samir Rachid Zaim & Mark-Phillip Pebworth & Imran McGrath & Lauren Okada & Morgan Weiss & Julian Reading & Julie L. Czartoski & Troy R. Torgerson & M. Juliana McElrath & Thomas F. Bumol & Peter J. Ske, 2024. "MOCHA’s advanced statistical modeling of scATAC-seq data enables functional genomic inference in large human cohorts," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    10. Derek Wong & Maha Tageldein & Ping Luo & Erik Ensminger & Jeffrey Bruce & Leslie Oldfield & Haifan Gong & Nicholas William Fischer & Brianne Laverty & Vallijah Subasri & Scott Davidson & Reem Khan & A, 2024. "Cell-free DNA from germline TP53 mutation carriers reflect cancer-like fragmentation patterns," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    11. Erica Butti & Stefano Cattaneo & Marco Bacigaluppi & Marco Cambiaghi & Giulia Maria Scotti & Elena Brambilla & Francesca Ruffini & Giacomo Sferruzza & Maddalena Ripamonti & Fabio Simeoni & Laura Cacci, 2022. "Neural precursor cells tune striatal connectivity through the release of IGFBPL1," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    12. Warren A. Cheung & Adam F. Johnson & William J. Rowell & Emily Farrow & Richard Hall & Ana S. A. Cohen & John C. Means & Tricia N. Zion & Daniel M. Portik & Christopher T. Saunders & Boryana Koseva & , 2023. "Direct haplotype-resolved 5-base HiFi sequencing for genome-wide profiling of hypermethylation outliers in a rare disease cohort," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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