Abstract
SummaryUsing chromatin conformation capture, we show that an enhancer cluster in the STARD10 type 2 diabetes (T2D) locus forms a defined 3-dimensional (3D) chromatin domain. A 4.1-kb region within this locus, carrying 5 T2D-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 the FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of the associated enhancer, from human pancreas-derived EndoC-βH1 cells impairs glucose-stimulated insulin secretion. Expression of both STARD10 and FCHSD2 is reduced in cells harboring CRISPR deletions, and lower expression of STARD10 and FCHSD2 is associated, the latter nominally, with the possession of risk variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2, but not ARAP1, impairs regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence β cell function.
Highlights
Genome-wide association studies (GWAS) have identified >400 genetic signals across >200 loci that associate with type 2 diabetes (T2D) risk (Mahajan et al, 2014, 2018; Morris et al, 2012; Scott et al, 2017; Spracklen et al, 2020; Voight et al, 2010)
Chromatin landscape at the STARD10 locus We investigated regulatory regions at the T2D GWAS locus close to STARD10 by overlaying multiple human islet epigenomic datasets: ATAC-seq, histone marks associated with active chromatin (i.e., H3K27ac), and chromatin immunoprecipitation sequencing (ChIP-seq) for key islet transcription factors (TFs) (Miguel-Escalada et al, 2019; Pasquali et al, 2014)
Credible set variants exhibit differential transcription factor binding and transcriptional activity We turned our attention to the five variants in the credible set with the greatest causal probability, as defined previously by fine mapping and functional GWAS (fGWAS) analysis (Carrat et al, 2017)
Summary
Genome-wide association studies (GWAS) have identified >400 genetic signals across >200 loci that associate with type 2 diabetes (T2D) risk (Mahajan et al, 2014, 2018; Morris et al, 2012; Scott et al, 2017; Spracklen et al, 2020; Voight et al, 2010). Data from these and other studies indicate that islet dysfunction plays a major role in T2D genetic risk. Genetic variants in islet enhancer clusters may contribute to diabetes risk by
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