RT Journal Article
SR Electronic
T1 Single cell chromatin accessibility reveals pancreatic islet cell type- and state-specific regulatory programs of diabetes risk
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 693671
DO 10.1101/693671
A1 Joshua Chiou
A1 Chun Zeng
A1 Zhang Cheng
A1 Jee Yun Han
A1 Michael Schlichting
A1 Serina Huang
A1 Jinzhao Wang
A1 Yinghui Sui
A1 Allison Deogaygay
A1 Mei-Lin Okino
A1 Yunjiang Qiu
A1 Ying Sun
A1 Parul Kudtarkar
A1 Rongxin Fang
A1 Sebastian Preissl
A1 Maike Sander
A1 David Gorkin
A1 Kyle J Gaulton
YR 2019
UL http://biorxiv.org/content/early/2019/07/09/693671.abstract
AB Genetic risk variants for complex, multifactorial diseases are enriched in cis-regulatory elements. Single cell epigenomic technologies create new opportunities to dissect cell type-specific mechanisms of risk variants, yet this approach has not been widely applied to disease-relevant tissues. Given the central role of pancreatic islets in type 2 diabetes (T2D) pathophysiology, we generated accessible chromatin profiles from 14.2k islet cells and identified 13 cell clusters including multiple alpha, beta and delta cell clusters which represented hormone-producing and signal-responsive cell states. We cataloged 244,236 islet cell type accessible chromatin sites and identified transcription factors (TFs) underlying both lineage- and state-specific regulation. We measured the enrichment of T2D and glycemic trait GWAS for the accessible chromatin profiles of single cells, which revealed heterogeneity in the effects of beta cell states and TFs on fasting glucose and T2D risk. We further used machine learning to predict the cell type-specific regulatory function of genetic variants, and single cell co-accessibility to link distal sites to putative cell type-specific target genes. We localized 239 fine-mapped T2D risk signals to islet accessible chromatin, and further prioritized variants at these signals with predicted regulatory function and co-accessibility with target genes. At the KCNQ1 locus, the causal T2D variant rs231361 had predicted effects on an enhancer with beta cell-specific, long-range co-accessibility to the insulin promoter, and deletion of this enhancer reduced insulin gene and protein expression in human embryonic stem cell-derived beta cells. Our findings provide a cell type- and state-resolved map of gene regulation in human islets, illuminate likely mechanisms of T2D risk at hundreds of loci, and demonstrate the power of single cell epigenomics for interpreting complex disease genetics.