Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a new regulator of insulin secretion

SUMMARYGenome-wide association studies have identified thousands of genetic variants associated with type 2 diabetes (T2D) risk. Using chromatin conformation capture we show that an enhancer cluster in the STARD10 T2D locus forms a defined 3D chromatin domain. A 4.1 Kb region within this region, carrying five disease-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of an associated enhancer, in human pancreatic beta cells impaired glucose-stimulated insulin secretion. Expression of both STARD10 and FCHSD2, but not ARAP1, was reduced in cells harboring CRISPR deletions, and expression of STARD10 and FCHSD2 was associated with the possession of variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2 impaired regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence β cell function.