Open AccessSingle-cell chromatin accessibility identifies pancreatic islet cell type– and state-specific regulatory programs of diabetes risk
Author(s) -
Joshua Chiou,
Chun Zeng,
Cheng Zhang,
Jee Yun Han,
Michael Schlichting,
Michael Miller,
Robert Mendez,
Serina Huang,
Jinzhao Wang,
Yinghui Sui,
Allison Deogaygay,
Mei-Lin Okino,
Yunjiang Qiu,
Ying Sun,
Parul Kudtarkar,
Rongxin Fang,
Sebastian Preißl,
Maike Sander,
David U. Gorkin,
Kyle J. Gaulton
Publication year - 2021
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-021-00823-0
Subject(s) - chromatin , biology , enhancer , epigenomics , cell type , genetics , transcription factor , islet , computational biology , genome , gene , cell , insulin , gene expression , endocrinology , dna methylation
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.