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Genetic determinants of co-accessible chromatin regions in activated T cells across humans
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Abstract
Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression.
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“Second, it has been recently shown that the variants associated with chromatin accessibility capture stimulus-sensitive signals and explain a significant proportion of heritability, even more so than eQTLs47,48.”
From A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles (2020) · cites this paper as [48]
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Sey, N. Y. A., Hu, B., Mah, W., Fauni, H., McAfee, J. C., Rajarajan, P., Brennand, K. J., Akbarian, S., & Won, H. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0603-0 · Cited by 297
Landscape of stimulation-responsive chromatin across diverse human immune cells
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Metadata
- Authors
- Gate, R. E., Cheng, C. S., Aiden, A. P., Siba, A., Tabaka, M., Lituiev, D., Machol, I., Gordon, M. G., Subramaniam, M., Shamim, M., Hougen, K. L., Wortman, I., Huang, S.-C., Durand, N. C., Feng, T., De Jager, P. L., Chang, H. Y., Aiden, E. L., Benoist, C., Beer, M. A., Ye, C. J., & Regev, A.
- Affiliations
- University of California, San Francisco (US)
- Broad Institute (US)
- Baylor College of Medicine (US)
- Johns Hopkins University (US)
- Harvard University (US)
- Stanford University (US)
- Corresponding author
- Cheng, Christine S.
- Ye, Chun J.
- Regev, Aviv
- ORCID
- Venue
- Nature Genetics
- Published
- 2018-07-09
- Volume
- 50
- Issue
- 8
- Pages
- 1140-1150
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6097927
- OpenAlex
- W2837542075
- Cited by
- 181
- References
- 83
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 43 · 2023: 22 · 2022: 19 · 2021: 25 · 2020: 23 · 2019: 19 · 2018: 1
- FWCI
- 6.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (5rm1hg006193-10)
- National Human Genome Research Institute (U01HG012192, RM1‐HG006193, P50HG007735, U01HG009380, R01HG007348)
- National Cancer Institute (F32CA168253)
- National Institute of General Medical Sciences (T32GM067547)
- National Institute of Allergy and Infectious Diseases (R21AI133337)
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK096822)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR071522)
- 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 › Chromatin Remodeling and Cancer
- Keywords
- CD4+ T cells, cis-regulatory elements, chromatin accessibility, 3D genome organization, transcription factor binding sites, gene expression regulation, non-coding variants, T cell activation
- MeSH terms
- Adult, Autoimmune Diseases, Chromatin, Female, Gene Expression Regulation, Genotype, Humans, Male, Regulatory Sequences, Nucleic Acid, CD4-Positive T-Lymphocytes, Polymorphism, Single Nucleotide
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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