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

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 g...

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Veröffentlicht in:Nature genetics 2018-08, Vol.50 (8), p.1140-1150
Hauptverfasser: Gate, Rachel E., Cheng, Christine S., Aiden, Aviva P., Siba, Atsede, Tabaka, Marcin, Lituiev, Dmytro, Machol, Ido, Gordon, M. Grace, Subramaniam, Meena, Shamim, Muhammad, Hougen, Kendrick L., Wortman, Ivo, Huang, Su-Chen, Durand, Neva C., Feng, Ting, De Jager, Philip L., Chang, Howard Y., Aiden, Erez Lieberman, Benoist, Christophe, Beer, Michael A., Ye, Chun J., Regev, Aviv
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container_end_page 1150
container_issue 8
container_start_page 1140
container_title Nature genetics
container_volume 50
creator Gate, Rachel E.
Cheng, Christine S.
Aiden, Aviva P.
Siba, Atsede
Tabaka, Marcin
Lituiev, Dmytro
Machol, Ido
Gordon, M. Grace
Subramaniam, Meena
Shamim, Muhammad
Hougen, Kendrick L.
Wortman, Ivo
Huang, Su-Chen
Durand, Neva C.
Feng, Ting
De Jager, Philip L.
Chang, Howard Y.
Aiden, Erez Lieberman
Benoist, Christophe
Beer, Michael A.
Ye, Chun J.
Regev, Aviv
description 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. Analysis of ATAC-seq and RNA-seq data from stimulated T cells identifies genetic variants that disrupt transcription factor binding sites within ATAC-seq peaks. ATAC quantitative trait loci (ATAC-QTLs) are enriched for autoimmune disease-associated variants.
doi_str_mv 10.1038/s41588-018-0156-2
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Grace ; Subramaniam, Meena ; Shamim, Muhammad ; Hougen, Kendrick L. ; Wortman, Ivo ; Huang, Su-Chen ; Durand, Neva C. ; Feng, Ting ; De Jager, Philip L. ; Chang, Howard Y. ; Aiden, Erez Lieberman ; Benoist, Christophe ; Beer, Michael A. ; Ye, Chun J. ; Regev, Aviv</creator><creatorcontrib>Gate, Rachel E. ; Cheng, Christine S. ; Aiden, Aviva P. ; Siba, Atsede ; Tabaka, Marcin ; Lituiev, Dmytro ; Machol, Ido ; Gordon, M. Grace ; Subramaniam, Meena ; Shamim, Muhammad ; Hougen, Kendrick L. ; Wortman, Ivo ; Huang, Su-Chen ; Durand, Neva C. ; Feng, Ting ; De Jager, Philip L. ; Chang, Howard Y. ; Aiden, Erez Lieberman ; Benoist, Christophe ; Beer, Michael A. ; Ye, Chun J. ; Regev, Aviv</creatorcontrib><description>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. 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Grace</creatorcontrib><creatorcontrib>Subramaniam, Meena</creatorcontrib><creatorcontrib>Shamim, Muhammad</creatorcontrib><creatorcontrib>Hougen, Kendrick L.</creatorcontrib><creatorcontrib>Wortman, Ivo</creatorcontrib><creatorcontrib>Huang, Su-Chen</creatorcontrib><creatorcontrib>Durand, Neva C.</creatorcontrib><creatorcontrib>Feng, Ting</creatorcontrib><creatorcontrib>De Jager, Philip L.</creatorcontrib><creatorcontrib>Chang, Howard Y.</creatorcontrib><creatorcontrib>Aiden, Erez Lieberman</creatorcontrib><creatorcontrib>Benoist, Christophe</creatorcontrib><creatorcontrib>Beer, Michael A.</creatorcontrib><creatorcontrib>Ye, Chun J.</creatorcontrib><creatorcontrib>Regev, Aviv</creatorcontrib><title>Genetic determinants of co-accessible chromatin regions in activated T cells across humans</title><title>Nature genetics</title><addtitle>Nat Genet</addtitle><addtitle>Nat Genet</addtitle><description>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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Grace</au><au>Subramaniam, Meena</au><au>Shamim, Muhammad</au><au>Hougen, Kendrick L.</au><au>Wortman, Ivo</au><au>Huang, Su-Chen</au><au>Durand, Neva C.</au><au>Feng, Ting</au><au>De Jager, Philip L.</au><au>Chang, Howard Y.</au><au>Aiden, Erez Lieberman</au><au>Benoist, Christophe</au><au>Beer, Michael A.</au><au>Ye, Chun J.</au><au>Regev, Aviv</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic determinants of co-accessible chromatin regions in activated T cells across humans</atitle><jtitle>Nature genetics</jtitle><stitle>Nat Genet</stitle><addtitle>Nat Genet</addtitle><date>2018-08-01</date><risdate>2018</risdate><volume>50</volume><issue>8</issue><spage>1140</spage><epage>1150</epage><pages>1140-1150</pages><issn>1061-4036</issn><eissn>1546-1718</eissn><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. Analysis of ATAC-seq and RNA-seq data from stimulated T cells identifies genetic variants that disrupt transcription factor binding sites within ATAC-seq peaks. ATAC quantitative trait loci (ATAC-QTLs) are enriched for autoimmune disease-associated variants.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>29988122</pmid><doi>10.1038/s41588-018-0156-2</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-9955-3809</orcidid><orcidid>https://orcid.org/0000-0002-9459-4393</orcidid><orcidid>https://orcid.org/0000-0002-2600-5147</orcidid><orcidid>https://orcid.org/0000-0002-8057-2505</orcidid><orcidid>https://orcid.org/0000-0003-4321-9187</orcidid><orcidid>https://orcid.org/0000-0003-0543-0758</orcidid><orcidid>https://orcid.org/0000-0001-6560-3783</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1061-4036
ispartof Nature genetics, 2018-08, Vol.50 (8), p.1140-1150
issn 1061-4036
1546-1718
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6097927
source MEDLINE; Nature Journals Online; SpringerLink Journals - AutoHoldings
subjects 38
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Accessibility
Adult
Agriculture
Animal Genetics and Genomics
Autoimmune diseases
Autoimmune Diseases - genetics
Biochemistry
Bioinformatics
Biological determinism
Biomedical and Life Sciences
Biomedicine
Cancer Research
CD4 antigen
CD4-Positive T-Lymphocytes - physiology
Chromatin
Chromatin - genetics
Disease
DNA methylation
Female
Gene expression
Gene Expression Regulation
Gene Function
Gene regulation
Genes
Genetic diversity
Genetic regulation
Genetic variance
Genomes
Genotype
Health
Human Genetics
Humans
Lymphocytes
Lymphocytes T
Male
Medical law
Polymorphism, Single Nucleotide
Quantitative genetics
Quantitative trait loci
Regulatory sequences
Regulatory Sequences, Nucleic Acid
Ribonucleic acid
RNA
Stem cells
T cells
Transcription (Genetics)
title Genetic determinants of co-accessible chromatin regions in activated T cells across humans
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