Ontology highlight
ABSTRACT: 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.
SUBMITTER: Burren OS
PROVIDER: S-EPMC5584004 | biostudies-literature | 2017 Sep
REPOSITORIES: biostudies-literature
Burren Oliver S OS Rubio García Arcadio A Javierre Biola-Maria BM Rainbow Daniel B DB Cairns Jonathan J Cooper Nicholas J NJ Lambourne John J JJ Schofield Ellen E Castro Dopico Xaquin X Ferreira Ricardo C RC Coulson Richard R Burden Frances F Rowlston Sophia P SP Downes Kate K Wingett Steven W SW Frontini Mattia M Ouwehand Willem H WH Fraser Peter P Spivakov Mikhail M Todd John A JA Wicker Linda S LS Cutler Antony J AJ Wallace Chris C
Genome biology 20170904 1
<h4>Background</h4>Autoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4<sup>+</sup> T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes.<h4>Results</h4>Within 4 h, activation of CD4<sup>+</sup> T cells invokes changes in histone modifications and enhancer RNA transcription that correspond to altered expression of the interacting genes i ...[more]