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

View ORCID ProfileJoshua Chiou, Chun Zeng, Zhang Cheng, Jee Yun Han, Michael Schlichting, Serina Huang, Jinzhao Wang, Yinghui Sui, Allison Deogaygay, Mei-Lin Okino, Yunjiang Qiu, Ying Sun, Parul Kudtarkar, Rongxin Fang, Sebastian Preissl, Maike Sander, David Gorkin, View ORCID ProfileKyle J Gaulton
doi: https://doi.org/10.1101/693671
Joshua Chiou
1Biomedical Graduate Studies Program, University of California San Diego, La Jolla CA
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  • ORCID record for Joshua Chiou
Chun Zeng
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA
3Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla CA
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Zhang Cheng
4Center for Epigenomics, University of California San Diego, La Jolla CA
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Jee Yun Han
4Center for Epigenomics, University of California San Diego, La Jolla CA
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Michael Schlichting
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA
3Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla CA
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Serina Huang
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA
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Jinzhao Wang
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA
3Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla CA
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Yinghui Sui
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA
3Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla CA
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Allison Deogaygay
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA
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Mei-Lin Okino
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA
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Yunjiang Qiu
3Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla CA
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Ying Sun
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA
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Parul Kudtarkar
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA
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Rongxin Fang
3Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla CA
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Sebastian Preissl
4Center for Epigenomics, University of California San Diego, La Jolla CA
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Maike Sander
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA
3Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla CA
5Institute for Genomic Medicine, University of California San Diego, La Jolla CA
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  • For correspondence: kgaulton@ucsd.edu dgorkin@ucsd.edu masander@ucsd.edu
David Gorkin
4Center for Epigenomics, University of California San Diego, La Jolla CA
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  • For correspondence: kgaulton@ucsd.edu dgorkin@ucsd.edu masander@ucsd.edu
Kyle J Gaulton
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA
5Institute for Genomic Medicine, University of California San Diego, La Jolla CA
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  • ORCID record for Kyle J Gaulton
  • For correspondence: kgaulton@ucsd.edu dgorkin@ucsd.edu masander@ucsd.edu
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Abstract

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.

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Posted July 09, 2019.
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Single cell chromatin accessibility reveals pancreatic islet cell type- and state-specific regulatory programs of diabetes risk
Joshua Chiou, Chun Zeng, Zhang Cheng, Jee Yun Han, Michael Schlichting, Serina Huang, Jinzhao Wang, Yinghui Sui, Allison Deogaygay, Mei-Lin Okino, Yunjiang Qiu, Ying Sun, Parul Kudtarkar, Rongxin Fang, Sebastian Preissl, Maike Sander, David Gorkin, Kyle J Gaulton
bioRxiv 693671; doi: https://doi.org/10.1101/693671
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Single cell chromatin accessibility reveals pancreatic islet cell type- and state-specific regulatory programs of diabetes risk
Joshua Chiou, Chun Zeng, Zhang Cheng, Jee Yun Han, Michael Schlichting, Serina Huang, Jinzhao Wang, Yinghui Sui, Allison Deogaygay, Mei-Lin Okino, Yunjiang Qiu, Ying Sun, Parul Kudtarkar, Rongxin Fang, Sebastian Preissl, Maike Sander, David Gorkin, Kyle J Gaulton
bioRxiv 693671; doi: https://doi.org/10.1101/693671

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