GSE160472
Single-cell chromatin accessibility identifies pancreatic islet cell type– and state-specific regulatory programs of diabetes risk [snATAC-seq]
Single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) creates new opportunities to dissect cell type–specific mechanisms of complex diseases. Since pancreatic islets are central to type 2 diabetes (T2D), we profiled 15,298 islet cells by using combinatorial barcoding snATAC-seq and identified 12 clusters, including multiple alpha, beta and delta cell states. We cataloged 228,873 accessible chromatin sites and identified transcription factors underlying lineage- and state-specific regulation. We observed state-specific enrichment of fasting glucose and T2D genome-wide association studies for beta cells and enrichment for other endocrine cell types. At T2D signals localized to islet-accessible chromatin, we prioritized variants with predicted regulatory function and co-accessibility with target genes. A causal T2D variant rs231361 at the KCNQ1 locus had predicted effects on a beta cell enhancer co-accessible with INS and genome editing in embryonic stem cell–derived beta cells affected INS levels. Together our findings demonstrate the power of single-cell epigenomics for interpreting complex disease genetics. Overall design: Single nucleus ATAC-seq of purified pancreatic islets from 3 human donors and whole pancreas from 1 human donor. Note: Supplementary files GSE160472_islet_snATAC.cluster_labels.txt.gz and GSE160472_islet_snATAC.merged_sites.bed.gz are results of the analysis only including the 3 islet samples.