Single-cell chromatin accessibility identifies pancreatic islet cell type– and state-specific regulatory programs of diabetes risk
In: Nature Genetics, Jg. 53 (2021-04-01), Heft 4
Online
academicJournal
- 455 - 466
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.
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Single-cell chromatin accessibility identifies pancreatic islet cell type– and state-specific regulatory programs of diabetes risk
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Autor/in / Beteiligte Person: | 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 |
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Zeitschrift: | Nature Genetics, Jg. 53 (2021-04-01), Heft 4 |
Veröffentlichung: | eScholarship, University of California, 2021 |
Medientyp: | academicJournal |
Umfang: | 455 - 466 |
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