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    Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis

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    Authors
    Yang, Jing
    McGovern, Amanda; orcid: 0000-0001-7727-3283
    Martin, Paul; orcid: 0000-0002-1016-6851
    Duffus, Kate
    Ge, Xiangyu
    Zarrineh, Peyman
    Morris, Andrew P.
    Adamson, Antony; orcid: 0000-0002-5408-0013
    Fraser, Peter; orcid: 0000-0002-0041-1227
    Rattray, Magnus; orcid: 0000-0001-8196-5565; email: magnus.rattray@manchester.ac.uk
    Eyre, Stephen; orcid: 0000-0002-1251-6974; email: steve.eyre@manchester.ac.uk
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    Publication Date
    2020-09-02
    Submitted date
    2019-10-22
    
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    Abstract
    Abstract: 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.
    Citation
    Nature Communications, volume 11, issue 1, page 4402
    Publisher
    Nature Publishing Group UK
    URI
    http://hdl.handle.net/10034/625755
    Type
    article
    Description
    From Springer Nature via Jisc Publications Router
    History: received 2019-10-22, accepted 2020-08-06, registration 2020-08-11, pub-electronic 2020-09-02, online 2020-09-02, collection 2020-12
    Publication status: Published
    Funder: RCUK | MRC | Medical Research Foundation; doi: https://doi.org/10.13039/501100009187; Grant(s): MR/N00017X/1
    Funder: Arthritis Research UK; doi: https://doi.org/10.13039/501100000341; Grant(s): 21754
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