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Index and biological spectrum of human DNase I hypersensitive sites
Open accessPublished version of a preprint
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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“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]
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“A majority of TCs (90%) were supported by FANTOM5 CAGE peaks17 and/or open chromatin regions from ENCODE22 and TCGA7”
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Metadata
- 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
- ORCID
- Venue
- Nature
- Published
- 2020-07-29
- Volume
- 584
- Issue
- 7820
- Pages
- 244-251
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7422677
- 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
- hybrid
- doi.org
- 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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