Single-cell chromatin accessibility identifies pancreatic islet cell type– and state-specific regulatory programs of diabetes risk

• Published in: Nature genetics Vol. 53; no. 4; pp. 455 - 466
• Main Authors: Chiou, Joshua, Zeng, Chun, Cheng, Zhang, Han, Jee Yun, Schlichting, Michael, Miller, Michael, Mendez, Robert, Huang, Serina, Wang, Jinzhao, Sui, Yinghui, Deogaygay, Allison, Okino, Mei-Lin, Qiu, Yunjiang, Sun, Ying, Kudtarkar, Parul, Fang, Rongxin, Preissl, Sebastian, Sander, Maike, Gorkin, David U., Gaulton, Kyle J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2021; Nature Publishing Group
• Subjects: 45/23; 631/114/1314; 631/208/177; 692/699/2743/137/773; Accessibility; Agriculture; Animal Genetics and Genomics; Beta cells; Biomedical and Life Sciences; Biomedicine; Blood Glucose - metabolism; Cancer Research; Cell Differentiation; Chromatin; Chromatin - chemistry; Chromatin - metabolism; Combinatorial analysis; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Disease; Epigenomics; Fasting; Gene expression; Gene Expression Profiling; Gene Function; Genetic aspects; Genetic regulation; Genetic research; Genetics; Genome editing; Genome-wide association studies; Genome-Wide Association Study; Genomes; Glucagon-Secreting Cells - metabolism; Glucagon-Secreting Cells - pathology; Health risk assessment; Health risks; High-Throughput Nucleotide Sequencing; Human Embryonic Stem Cells - cytology; Human Genetics; Humans; Identification and classification; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Islet cells; KCNQ1 Potassium Channel - genetics; KCNQ1 Potassium Channel - metabolism; KCNQ1 protein; Multigene Family; Pancreas; Pancreatic beta cells; Pancreatic Polypeptide-Secreting Cells - metabolism; Pancreatic Polypeptide-Secreting Cells - pathology; Polymorphism, Genetic; Potassium channels (voltage-gated); Risk factors; Single-Cell Analysis; Somatostatin-Secreting Cells - metabolism; Somatostatin-Secreting Cells - pathology; Structure; Transcription factors; Transcription Factors - classification; Transcription Factors - genetics; Transcription Factors - metabolism; Transposase; Type 2 diabetes; United States
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-021-00823-0

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. Single-cell ATAC-seq analysis of human pancreatic islet cells identifies different cell clusters and transcription factors that underlie lineage- and state-specific regulation and helps prioritize type 2 diabetes risk variants.