Cited by 334Genomics and Chromatin DynamicsGenetic Associations and EpidemiologyEpigenetics and DNA Methylation

Index and biological spectrum of human DNase I hypersensitive sites

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Meuleman, Wouter, Muratov, Alexander, Rynes, Eric, Halow, Jessica, Lee, Kristen, Bates, Daniel, Diegel, Morgan, Dunn, Douglas +12 more·2020·Nature

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Abstract

DNase I hypersensitive sites (DHSs) are generic markers of regulatory DNA 1–5 and contain genetic variations associated with diseases and phenotypic traits 6–8 . 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.

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  • Open chromatin regions are not limited to active enhancers, and also harbour active gene promoters, regulatory elements in a poised chromatin configuration, and some structural regions such as tissue-invariant binding sites for CTCF.

    “However, open chromatin regions are not limited to active enhancers, and also harbour other regions including active gene promoters, regulatory elements in a ‘poised’ chromatin configuration (discussed below), as well as some structural regions such as tissue-invariant binding sites for the architectural protein CCCTC-binding factor (CTCF) [129–132].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [130]

    The Introduction (page unavailable) identifies promoters and chromatin insulators among the active regulatory elements marked by accessible DNA, and says DHSs can appear before functional activation. This supports the claim that open chromatin is not limited to active enhancers, but our copy does not specifically identify poised chromatin configurations or tissue-invariant CTCF-binding sites as examples. (LLM, conf=0.84)

    Experimental — accuracy not yet measured
  • A majority of TCs (90%) were supported by FANTOM5 CAGE peaks and/or open chromatin regions from ENCODE and TCGA.

    “A majority of TCs (90%) were supported by FANTOM5 CAGE peaks17 and/or open chromatin regions from ENCODE22 and TCGA7”

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Research works printed but not linked: 1

  1. [15]Sabo PJ Genome-scale mapping of DNase I sensitivity in vivo using tiling DNA microarrays. Nat. Methods 3, 511– 518 (2006). 16791208

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Authors
Meuleman, W., Muratov, A., Rynes, E., Halow, J., Lee, K., Bates, D., Diegel, M., Dunn, D., Neri, F., Teodosiadis, A., Reynolds, A., Haugen, E., Nelson, J., Johnson, A., Frerker, M., Buckley, M., Sandstrom, R., Vierstra, J., Kaul, R., & Stamatoyannopoulos, J.
Affiliations
  • Altius Institute for Biomedical Sciences (US)
  • University of Washington (US)
Corresponding author
  • Meuleman, Wouter
  • Stamatoyannopoulos, John
Venue
Nature
Published
2020-07-29
Volume
584
Issue
7820
Pages
244-251
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W3046013264
Cited by
331
References
60
Citations by year
2026: 40 · 2025: 59 · 2024: 61 · 2023: 58 · 2022: 56 · 2021: 43 · 2020: 14
Type
paratext
Language
en
Open access
Locations
  • Nature (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
National Human Genome Research Institute (U54HG007010, UM1HG009444, R35HG011317)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
DNase I hypersensitive sites, cis-regulatory elements, genetic association signals, heritability
MeSH terms
Chromatin, Deoxyribonuclease I, DNA, Gene Expression Regulation, Genes, Humans, Promoter Regions, Genetic, Regulatory Sequences, Nucleic Acid, Genome, Human, Molecular Sequence Annotation

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