Chromatin 3D Interaction Analysis of the <i>STARD10</i> Locus Unveils <i>FCHSD2</i> as a New Regulator of Insulin Secretion

Abstract

Genome-wide association studies have identified hundreds 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 identified FCHSD2 as an additional target of the enhancer cluster. Deletion of the variant region, or an associated enhancer (R2), from EndoC-βH1 cells using CRISPR-Cas9 reduced STARD10 and FCHSD2, but not neighboring ARAP1 expression, and impaired glucose-stimulated insulin secretion. Correspondingly, CRISPR-Cas9-mediated knockout of STARD10 or FCHSD2 impaired secretion. Finally, expression of STARD10 and FCHSD2 in human islets was associated with the possession of variant alleles. Thus, multiple genes at the STARD10 locus influence β cell function to alter disease risk.