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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 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.

Original publication

DOI

10.1186/s13059-017-1285-0

Type

Journal article

Journal

Genome Biol

Publication Date

04/09/2017

Volume

18

Keywords

Autoimmune disease, CD4+ T cell activation, CD4+ T cells, Chromatin conformation, Genetics, Genome-wide association studies, Genomics, Autoimmune Diseases, CD4-Positive T-Lymphocytes, Chromatin, Chromosome Mapping, Enhancer Elements, Genetic, Humans, Interleukin-2 Receptor alpha Subunit, Lymphocyte Activation, Promoter Regions, Genetic, Transcriptome