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Chromosome contacts in activated T cells identify autoimmune disease candidate genes

BACKGROUND: Autoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4(+) T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes. RESULTS: Within 4...

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Autores principales: Burren, Oliver S., Rubio García, Arcadio, Javierre, Biola-Maria, Rainbow, Daniel B., Cairns, Jonathan, Cooper, Nicholas J., Lambourne, John J., Schofield, Ellen, Castro Dopico, Xaquin, Ferreira, Ricardo C., Coulson, Richard, Burden, Frances, Rowlston, Sophia P., Downes, Kate, Wingett, Steven W., Frontini, Mattia, Ouwehand, Willem H., Fraser, Peter, Spivakov, Mikhail, Todd, John A., Wicker, Linda S., Cutler, Antony J., Wallace, Chris
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584004/
https://www.ncbi.nlm.nih.gov/pubmed/28870212
http://dx.doi.org/10.1186/s13059-017-1285-0
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author Burren, Oliver S.
Rubio García, Arcadio
Javierre, Biola-Maria
Rainbow, Daniel B.
Cairns, Jonathan
Cooper, Nicholas J.
Lambourne, John J.
Schofield, Ellen
Castro Dopico, Xaquin
Ferreira, Ricardo C.
Coulson, Richard
Burden, Frances
Rowlston, Sophia P.
Downes, Kate
Wingett, Steven W.
Frontini, Mattia
Ouwehand, Willem H.
Fraser, Peter
Spivakov, Mikhail
Todd, John A.
Wicker, Linda S.
Cutler, Antony J.
Wallace, Chris
author_facet Burren, Oliver S.
Rubio García, Arcadio
Javierre, Biola-Maria
Rainbow, Daniel B.
Cairns, Jonathan
Cooper, Nicholas J.
Lambourne, John J.
Schofield, Ellen
Castro Dopico, Xaquin
Ferreira, Ricardo C.
Coulson, Richard
Burden, Frances
Rowlston, Sophia P.
Downes, Kate
Wingett, Steven W.
Frontini, Mattia
Ouwehand, Willem H.
Fraser, Peter
Spivakov, Mikhail
Todd, John A.
Wicker, Linda S.
Cutler, Antony J.
Wallace, Chris
author_sort Burren, Oliver S.
collection PubMed
description BACKGROUND: Autoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4(+) T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes. RESULTS: Within 4 h, activation of CD4(+) T cells invokes changes in histone modifications and enhancer RNA transcription that correspond to altered expression of the interacting genes identified by promoter capture Hi-C. By integrating promoter capture Hi-C data with genetic associations for five autoimmune diseases, we prioritised 245 candidate genes with a median distance from peak signal to prioritised gene of 153 kb. Just under half (108/245) prioritised genes related to activation-sensitive interactions. This included IL2RA, where allele-specific expression analyses were consistent with its interaction-mediated regulation, illustrating the utility of the approach. CONCLUSIONS: Our systematic experimental framework offers an alternative approach to candidate causal gene identification for variants with cell state-specific functional effects, with achievable sample sizes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-017-1285-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-55840042017-09-06 Chromosome contacts in activated T cells identify autoimmune disease candidate genes Burren, Oliver S. Rubio García, Arcadio Javierre, Biola-Maria Rainbow, Daniel B. Cairns, Jonathan Cooper, Nicholas J. Lambourne, John J. Schofield, Ellen Castro Dopico, Xaquin Ferreira, Ricardo C. Coulson, Richard Burden, Frances Rowlston, Sophia P. Downes, Kate Wingett, Steven W. Frontini, Mattia Ouwehand, Willem H. Fraser, Peter Spivakov, Mikhail Todd, John A. Wicker, Linda S. Cutler, Antony J. Wallace, Chris Genome Biol Research BACKGROUND: Autoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4(+) T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes. RESULTS: Within 4 h, activation of CD4(+) T cells invokes changes in histone modifications and enhancer RNA transcription that correspond to altered expression of the interacting genes identified by promoter capture Hi-C. By integrating promoter capture Hi-C data with genetic associations for five autoimmune diseases, we prioritised 245 candidate genes with a median distance from peak signal to prioritised gene of 153 kb. Just under half (108/245) prioritised genes related to activation-sensitive interactions. This included IL2RA, where allele-specific expression analyses were consistent with its interaction-mediated regulation, illustrating the utility of the approach. CONCLUSIONS: Our systematic experimental framework offers an alternative approach to candidate causal gene identification for variants with cell state-specific functional effects, with achievable sample sizes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-017-1285-0) contains supplementary material, which is available to authorized users. BioMed Central 2017-09-04 /pmc/articles/PMC5584004/ /pubmed/28870212 http://dx.doi.org/10.1186/s13059-017-1285-0 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Burren, Oliver S.
Rubio García, Arcadio
Javierre, Biola-Maria
Rainbow, Daniel B.
Cairns, Jonathan
Cooper, Nicholas J.
Lambourne, John J.
Schofield, Ellen
Castro Dopico, Xaquin
Ferreira, Ricardo C.
Coulson, Richard
Burden, Frances
Rowlston, Sophia P.
Downes, Kate
Wingett, Steven W.
Frontini, Mattia
Ouwehand, Willem H.
Fraser, Peter
Spivakov, Mikhail
Todd, John A.
Wicker, Linda S.
Cutler, Antony J.
Wallace, Chris
Chromosome contacts in activated T cells identify autoimmune disease candidate genes
title Chromosome contacts in activated T cells identify autoimmune disease candidate genes
title_full Chromosome contacts in activated T cells identify autoimmune disease candidate genes
title_fullStr Chromosome contacts in activated T cells identify autoimmune disease candidate genes
title_full_unstemmed Chromosome contacts in activated T cells identify autoimmune disease candidate genes
title_short Chromosome contacts in activated T cells identify autoimmune disease candidate genes
title_sort chromosome contacts in activated t cells identify autoimmune disease candidate genes
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584004/
https://www.ncbi.nlm.nih.gov/pubmed/28870212
http://dx.doi.org/10.1186/s13059-017-1285-0
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