Human islet open chromatin profiling reveals epigenomic changes elicited by genetic and environmental factors. Homo sapiens

Type 2 Diabetes (T2D) is a complex disorder with both genetic and environmental risk factors. The epigenome integrates these factors to control transcriptional regulatory programs under steady state, stimulatory, and pathogenic conditions. However, knowledge of how genetic and environmental factors alter the islet chromatin/regulatory landscape is limited. To fill this knowledge gap and to assess the genome-wide effects of SNVs and the diabetic state on islet chromatin accessibility and regulatory element (RE) use, we measured and compared islet chromatin accessibility patterns from 19 genotyped individuals (14 non-diabetic [ND] and 5 T2D) using ATAC-seq. Chromatin accessibility quantitative trait locus (caQTL) analyses identified 3001 SNVs that alter putative RE use/activity. Islet caQTL were significantly and specifically enriched in islet stretch enhancers and islet transcription factor binding motifs, such as FOXA2, NKX6.1, RFX5, and PDX1. Moreover, islet caQTLs were enriched in T2D and fasting glucose-related GWAS loci, including SNVs associated with altered islet expression of ADCY5, MTNR1B, and ZMIZ1. For X/Y sequences tested, the allelic effect on chromatin accessibility matched enhancer activity in luciferase reporter assays. As anticipated, T2D islets did not exhibit concerted, dramatic shifts in chromatin accessibility compared to ND islets. Motif analysis of the 1882 sites exhibiting modest but significant chromatin accessibility changes revealed suggesting that which were roles in responding to oxidative stress, such as BACH1, BACH2 and NRF2. Together, these results provide new insights into the relative impact of genetic and environmental perturbation on the islet epigenome and chromatin-based evidence that a subset of T2D-associated functional variant(s) and their direction-of-effect underlying genetic association with T2D and islet dysfunction. the genetic and environmental Our study uncovers chromatin accessibility signatures of T2D, highlighting the central role of oxidative stress in the etiology of T2D, and provides insights into how T2D associated SNPs modulate the activity of REs in human islets.