10.17863/CAM.12199
Burren, Oliver
0000-0002-3388-5760
garcia, AR
javierre, B-M
rainbow, DB
cairns, J
cooper, NJ
Lambourne, John
0000-0003-2460-0759
schofield, E
dopico, X
ferreira, RC
coulson, R
burden, F
rowlston, SP
Downes, Kate
0000-0003-0366-1579
wingett, S
Frontini, Mattia
0000-0001-8074-6299
Ouwehand, Willem
0000-0002-7744-1790
fraser, P
spivakov, M
todd, JA
wicker, LS
cutler, AJ
Wallace, Chris
0000-0001-9755-1703
Chromosome contacts in activated T cells identify autoimmune disease candidate genes
Apollo - University of Cambridge Repository (staging)
2017
Genetics
Genomics
Chromatin conformation
CD4+ T cells
CD4+ T cell activation
Autoimmune disease
Genome-wide association studies
Apollo - University of Cambridge Repository (staging)
Apollo - University of Cambridge Repository (staging)
2017-09-29
2017-09-29
Article
1474-7596
https://www.repository.cam.ac.uk/handle/1810/267447
1474-760X
10.1186/s13059-017-1285-0
Attribution 4.0 International
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.
This work was funded by the JDRF (9-2011-253), the Wellcome Trust (089989, 091157, 107881), the UK Medical Research Council (MR/L007150/1, MC_UP_1302/5), the UK Biotechnology and Biological Sciences Research Council (BB/J004480/1) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. The research leading to these results has received funding from the European Union’s 7th Framework Programme (FP7/2007-2013) under grant agreement no. 241447 (NAIMIT). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140).
WELLCOME TRUST
107881/Z/15/Z
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