Chromosome contacts in activated T cells identify autoimmune disease candidate genes

Journal article

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.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.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.

Authors: Burren, O; Rubio García, A; Javierre, B; Rainbow, D; Cairns, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BioMed Central
• Journal: Genome Biology
• Volume: 18
• Issue: 1
• Article number: 165
• Publication date: 2017-09-04
• Acceptance date: 2017-07-21
• DOI: 10.1186/s13059-017-1285-0
• ISSN: 1474-760X
• Pmid: 28870212
• Language: English
• Keywords: genomics; genetics; CD4+ T cell activation; genome-wide association studies; CD4+ T cells; autoimmune disease; chromatin conformation