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Genome Biol. 2017 Sep 4;18(1):165. doi: 10.1186/s13059-017-1285-0.

Chromosome contacts in activated T cells identify autoimmune disease candidate genes.

Author information

1
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0SP, UK.
2
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
3
Present address: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
4
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
5
Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
6
National Health Service Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
7
British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
8
Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
9
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0SP, UK. cew54@cam.ac.uk.
10
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK. cew54@cam.ac.uk.
11
MRC Biostatistics Unit, University of Cambridge, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, CB2 0SR, UK. cew54@cam.ac.uk.

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.

KEYWORDS:

Autoimmune disease; CD4+ T cell activation; CD4+ T cells; Chromatin conformation; Genetics; Genome-wide association studies; Genomics

PMID:
28870212
PMCID:
PMC5584004
DOI:
10.1186/s13059-017-1285-0
[Indexed for MEDLINE]
Free PMC Article

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