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Nat Genet. 2018 Aug;50(8):1140-1150. doi: 10.1038/s41588-018-0156-2. Epub 2018 Jul 9.

Genetic determinants of co-accessible chromatin regions in activated T cells across humans.

Author information

1
Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
2
Biological and Medical Informatics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
3
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. chcheng@bu.edu.
4
Department of Biology, Boston University, Boston, MA, USA. chcheng@bu.edu.
5
Department of Molecular and Human Genetics, the Center for Genome Architecture, Baylor College of Medicine, Houston, TX, USA.
6
Department of Bioengineering, Rice University, Houston, TX, USA.
7
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
8
Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA.
9
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
10
Division of Immunology, Department of Microbiology and Immunology, Harvard Medical School, Boston, MA, USA.
11
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology and Psychiatry, Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
12
Harvard Medical School, Boston, MA, USA.
13
Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
14
Department of Computer Science, Rice University, Houston, TX, USA.
15
Department of Computational and Applied Mathematics, Rice University, Houston, TX, USA.
16
Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.
17
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
18
Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA. jimmie.ye@ucsf.edu.
19
Institute of Computational Health Sciences, University of California, San Francisco, San Francisco, CA, USA. jimmie.ye@ucsf.edu.
20
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. jimmie.ye@ucsf.edu.
21
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA. jimmie.ye@ucsf.edu.
22
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. aregev@broadinstitute.org.
23
Howard Hughes Medical Institute, Koch Institute of Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. aregev@broadinstitute.org.

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.

PMID:
29988122
PMCID:
PMC6097927
DOI:
10.1038/s41588-018-0156-2
[Indexed for MEDLINE]
Free PMC Article

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