Chromosome contacts in activated T cells identify autoimmune disease candidate genes
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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 four hours, 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 (PCHi-C). By integrating PCHi-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.
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1474-760X
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MRC (1185)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U01DK062418)
Wellcome Trust (089989/Z/09/Z)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (091157/Z/10/B)
Medical Research Council (MC_UU_00002/4)