Unravelling the t1D 3D genome to map functional targets of genetic risk

High resolution mapping of genetic risk by GWAS, eQTL and imputation has identified 52 regions of genetic risk for type 1 diabetes, and these loci are highly enriched for immune function. When combined with functional annotation data it is also clear that the genetic risk of T1D is highly enriched in non coding regulatory elements. This suggests that the genetic risk alters gene regulation in a significant number of cases, and the target genes controlled by theses enhancers now must be fine mapped in order to identify the actual targets of genetic variation in T1D. Given that functional regulatory elements in immune cells are enriched for genetic risk,, and regulatory T cells are implicated in the loss of tolerance in T1D,, we have intersected our FOXP3 CHIP data onto the genomics data and find that >70% of the T1D risk loci contain at least 1 FOXP3 binding site.. In order to determine whether these enhancers are driving altered function in Treg or Tconv, a high resolution map of enhancer targets is needed. This requires a new technology called Chromosome Conformation Capture, which can biochemically trap DNA when looped over short or long distances. The genome wide approach is called HiC, and we have performed a HiC experiment to map all of the enhancer contacts in Treg and Tconv cells. Functional annotation of the targets of enhancers linked to genetic risk will be presented, and putative interventions to restore immune function are to be extracted for testing.