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 |
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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 |
format | Article |
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+
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.</description><identifier>ISSN: 1061-4036</identifier><identifier>EISSN: 1546-1718</identifier><identifier>DOI: 10.1038/s41588-018-0156-2</identifier><identifier>PMID: 29988122</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>38 ; 38/91 ; 45 ; 45/23 ; 631/208/176 ; 631/208/191 ; 631/250 ; 631/553 ; 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)</subject><ispartof>Nature genetics, 2018-08, Vol.50 (8), p.1140-1150</ispartof><rights>The Author(s) 2018</rights><rights>COPYRIGHT 2018 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Aug 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c605t-c0b3ef33ebff9ae1ff4f268d57c9e0d88ced3804ecfa6d7a266f10124e3a29183</citedby><cites>FETCH-LOGICAL-c605t-c0b3ef33ebff9ae1ff4f268d57c9e0d88ced3804ecfa6d7a266f10124e3a29183</cites><orcidid>0000-0001-9955-3809 ; 0000-0002-9459-4393 ; 0000-0002-2600-5147 ; 0000-0002-8057-2505 ; 0000-0003-4321-9187 ; 0000-0003-0543-0758 ; 0000-0001-6560-3783</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41588-018-0156-2$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41588-018-0156-2$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29988122$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gate, Rachel E.</creatorcontrib><creatorcontrib>Cheng, Christine S.</creatorcontrib><creatorcontrib>Aiden, Aviva P.</creatorcontrib><creatorcontrib>Siba, Atsede</creatorcontrib><creatorcontrib>Tabaka, Marcin</creatorcontrib><creatorcontrib>Lituiev, Dmytro</creatorcontrib><creatorcontrib>Machol, Ido</creatorcontrib><creatorcontrib>Gordon, M. 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.
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.</description><subject>38</subject><subject>38/91</subject><subject>45</subject><subject>45/23</subject><subject>631/208/176</subject><subject>631/208/191</subject><subject>631/250</subject><subject>631/553</subject><subject>Accessibility</subject><subject>Adult</subject><subject>Agriculture</subject><subject>Animal Genetics and Genomics</subject><subject>Autoimmune diseases</subject><subject>Autoimmune Diseases - genetics</subject><subject>Biochemistry</subject><subject>Bioinformatics</subject><subject>Biological determinism</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>CD4 antigen</subject><subject>CD4-Positive T-Lymphocytes - physiology</subject><subject>Chromatin</subject><subject>Chromatin - genetics</subject><subject>Disease</subject><subject>DNA methylation</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Gene Function</subject><subject>Gene regulation</subject><subject>Genes</subject><subject>Genetic diversity</subject><subject>Genetic regulation</subject><subject>Genetic variance</subject><subject>Genomes</subject><subject>Genotype</subject><subject>Health</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Medical law</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Quantitative genetics</subject><subject>Quantitative trait loci</subject><subject>Regulatory sequences</subject><subject>Regulatory Sequences, Nucleic Acid</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Stem cells</subject><subject>T cells</subject><subject>Transcription (Genetics)</subject><issn>1061-4036</issn><issn>1546-1718</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNksFuFSEUhomxsbX1AdyYSdzUxVRgGGA2Jk2jtUmTJtq6cEO4zGEuzQxUYBp9exlvbXuNJoYAJ_Cdn5zDj9BLgo8IbuTbxEgrZY3JMlte0ydoj7SM10QQ-bTEmJOa4YbvoucpXWNMGMPyGdqlXScloXQPfT0FD9mZqocMcXJe-5yqYCsTam0MpORWI1RmHcOks_NVhMEFn6oSapPdrc7QV5eVgXFM5SSGlKr1PGmfDtCO1WOCF3f7Prr68P7y5GN9fnF6dnJ8XhuO21wbvGrANg2srO00EGuZpVz2rTAd4F5KA30jMQNjNe-Fppxbggll0GjaEdnso3cb3Zt5NUFvwOeoR3UT3aTjDxW0U9s33q3VEG4Vx53oqCgCh3cCMXybIWU1ubQUpD2EOSmKuSjtKktBX_-BXoc5-lKeooRzzBjryAM16BGU8zaUd80iqo5bQQXrBF6oo79QZfQwORM8WFfOtxLebCUUJsP3POg5JXX2-dP_sxdftlmyYX_9XgR73zuC1WI0tTGaKkZTi9EULTmvHjf9PuO3swpAN0AqV36A-NCpf6v-BJxZ3KM</recordid><startdate>20180801</startdate><enddate>20180801</enddate><creator>Gate, Rachel E.</creator><creator>Cheng, Christine S.</creator><creator>Aiden, Aviva P.</creator><creator>Siba, Atsede</creator><creator>Tabaka, Marcin</creator><creator>Lituiev, Dmytro</creator><creator>Machol, Ido</creator><creator>Gordon, M. 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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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c605t-c0b3ef33ebff9ae1ff4f268d57c9e0d88ced3804ecfa6d7a266f10124e3a29183</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>38</topic><topic>38/91</topic><topic>45</topic><topic>45/23</topic><topic>631/208/176</topic><topic>631/208/191</topic><topic>631/250</topic><topic>631/553</topic><topic>Accessibility</topic><topic>Adult</topic><topic>Agriculture</topic><topic>Animal Genetics and Genomics</topic><topic>Autoimmune diseases</topic><topic>Autoimmune Diseases - genetics</topic><topic>Biochemistry</topic><topic>Bioinformatics</topic><topic>Biological determinism</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>CD4 antigen</topic><topic>CD4-Positive T-Lymphocytes - physiology</topic><topic>Chromatin</topic><topic>Chromatin - genetics</topic><topic>Disease</topic><topic>DNA methylation</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Gene Function</topic><topic>Gene regulation</topic><topic>Genes</topic><topic>Genetic diversity</topic><topic>Genetic regulation</topic><topic>Genetic variance</topic><topic>Genomes</topic><topic>Genotype</topic><topic>Health</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Male</topic><topic>Medical law</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Quantitative genetics</topic><topic>Quantitative trait loci</topic><topic>Regulatory sequences</topic><topic>Regulatory Sequences, Nucleic Acid</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Stem cells</topic><topic>T cells</topic><topic>Transcription (Genetics)</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gate, Rachel E.</creatorcontrib><creatorcontrib>Cheng, Christine S.</creatorcontrib><creatorcontrib>Aiden, Aviva P.</creatorcontrib><creatorcontrib>Siba, Atsede</creatorcontrib><creatorcontrib>Tabaka, Marcin</creatorcontrib><creatorcontrib>Lituiev, Dmytro</creatorcontrib><creatorcontrib>Machol, Ido</creatorcontrib><creatorcontrib>Gordon, M. 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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> |
fulltext | fulltext |
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 38/91 45 45/23 631/208/176 631/208/191 631/250 631/553 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 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T17%3A55%3A25IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genetic%20determinants%20of%20co-accessible%20chromatin%20regions%20in%20activated%20T%20cells%20across%20humans&rft.jtitle=Nature%20genetics&rft.au=Gate,%20Rachel%20E.&rft.date=2018-08-01&rft.volume=50&rft.issue=8&rft.spage=1140&rft.epage=1150&rft.pages=1140-1150&rft.issn=1061-4036&rft.eissn=1546-1718&rft_id=info:doi/10.1038/s41588-018-0156-2&rft_dat=%3Cgale_pubme%3EA572749701%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2166044491&rft_id=info:pmid/29988122&rft_galeid=A572749701&rfr_iscdi=true |