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Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis
Genome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here,...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468106/ https://www.ncbi.nlm.nih.gov/pubmed/32879318 http://dx.doi.org/10.1038/s41467-020-18180-7 |
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author | Yang, Jing McGovern, Amanda Martin, Paul Duffus, Kate Ge, Xiangyu Zarrineh, Peyman Morris, Andrew P. Adamson, Antony Fraser, Peter Rattray, Magnus Eyre, Stephen |
author_facet | Yang, Jing McGovern, Amanda Martin, Paul Duffus, Kate Ge, Xiangyu Zarrineh, Peyman Morris, Andrew P. Adamson, Antony Fraser, Peter Rattray, Magnus Eyre, Stephen |
author_sort | Yang, Jing |
collection | PubMed |
description | Genome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T cells over 24 h, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes in gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including FOXO1, which we confirm using CRISPR/Cas9. |
format | Online Article Text |
id | pubmed-7468106 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-74681062020-09-16 Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis Yang, Jing McGovern, Amanda Martin, Paul Duffus, Kate Ge, Xiangyu Zarrineh, Peyman Morris, Andrew P. Adamson, Antony Fraser, Peter Rattray, Magnus Eyre, Stephen Nat Commun Article Genome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T cells over 24 h, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes in gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including FOXO1, which we confirm using CRISPR/Cas9. Nature Publishing Group UK 2020-09-02 /pmc/articles/PMC7468106/ /pubmed/32879318 http://dx.doi.org/10.1038/s41467-020-18180-7 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Yang, Jing McGovern, Amanda Martin, Paul Duffus, Kate Ge, Xiangyu Zarrineh, Peyman Morris, Andrew P. Adamson, Antony Fraser, Peter Rattray, Magnus Eyre, Stephen Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis |
title | Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis |
title_full | Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis |
title_fullStr | Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis |
title_full_unstemmed | Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis |
title_short | Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis |
title_sort | analysis of chromatin organization and gene expression in t cells identifies functional genes for rheumatoid arthritis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468106/ https://www.ncbi.nlm.nih.gov/pubmed/32879318 http://dx.doi.org/10.1038/s41467-020-18180-7 |
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