Chromosome contacts in activated T cells identify autoimmune disease candidate genes
Oliver S. Burren,
Arcadio Rubio García,
Daniel B. Rainbow,
Nicholas J. Cooper,
John J Lambourne,
Xaquin Castro Dopico,
Ricardo C Ferreira,
Sophia P Rowlston,
Steven W Wingett,
Willem H. Ouwehand,
John A Todd,
Linda S Wicker,
Antony J Cutler,
Posted 17 Jan 2017
bioRxiv DOI: 10.1101/100958 (published DOI: 10.1186/s13059-017-1285-0)
Posted 17 Jan 2017
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. 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.
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