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

Item Type:Article
Title:Single-cell chromatin accessibility identifies pancreatic islet cell type- and state-specific regulatory programs of diabetes risk
Creators Name:Chiou, J. and Zeng, C. and Cheng, Z. and Han, J.Y. and Schlichting, M. and Miller, M. and Mendez, R. and Huang, S. and Wang, J. and Sui, Y. and Deogaygay, A. and Okino, M.L. and Qiu, Y. and Sun, Y. and Kudtarkar, P. and Fang, R. and Preissl, S. and Sander, M. and Gorkin, D.U. and Gaulton, K.J.
Abstract: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.
Keywords:Data Processing, Epigenomics, Type 2 Diabetes
Source:Nature Genetics
ISSN:1061-4036
Publisher:Nature Publishing Group
Volume:53
Number:4
Page Range:455-466
Date:April 2021
Additional Information:Copyright © The Author(s), under exclusive licence to Springer Nature America, Inc. 2021
Official Publication:https://doi.org/10.1038/s41588-021-00823-0
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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