Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development.

Ryan J Geusz,P Duc Si Dong,Joseph J Lancman,Samy Kefalopoulou,Nichole Wetton,Maike Sander,Joshua Chiou,Jian Yan,Anthony Aylward,Bing Ren,Kyle J Gaulton,Allen Wang,Jinzhao Wang,Yunjiang Qiu

doi:10.7554/elife.59067

Ryan J Geusz, P Duc Si Dong + Show 12 more

Open Access

https://doi.org/10.7554/elife.59067

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Abstract

Genetic variants associated with type 2 diabetes (T2D) risk affect gene regulation in metabolically relevant tissues, such as pancreatic islets. Here, we investigated contributions of regulatory programs active during pancreatic development to T2D risk. Generation of chromatin maps from developmental precursors throughout pancreatic differentiation of human embryonic stem cells (hESCs) identifies enrichment of T2D variants in pancreatic progenitor-specific stretch enhancers that are not active in islets. Genes associated with progenitor-specific stretch enhancers are predicted to regulate developmental processes, most notably tissue morphogenesis. Through gene editing in hESCs, we demonstrate that progenitor-specific enhancers harboring T2D-associated variants regulate cell polarity genes LAMA1 and CRB2. Knockdown of lama1 or crb2 in zebrafish embryos causes a defect in pancreas morphogenesis and impairs islet cell development. Together, our findings reveal that a subset of T2D risk variants specifically affects pancreatic developmental programs, suggesting that dysregulation of developmental processes can predispose to T2D.

Highlights

Type 2 diabetes (T2D) is a multifactorial metabolic disorder characterized by insulin insensitivity and insufficient insulin secretion by pancreatic beta cells (Halban et al, 2014)
We identified type 2 diabetes (T2D)-associated variants localized in active enhancers in developmental precursors but not in mature islets, used genome editing in human embryonic stem cells (hESCs) to define target genes of pancreatic progenitor-specific enhancers harboring T2D variants, and employed zebrafish genetic models to study the role of two target genes in pancreatic and endocrine cell development
We identify T2D-associated variants localized within chromatin active in pancreatic progenitors but not islets or other T2D-relevant tissues, suggesting a novel mechanism whereby a subset of T2D risk variants alters pancreatic developmental processes

Summary

Introduction

Type 2 diabetes (T2D) is a multifactorial metabolic disorder characterized by insulin insensitivity and insufficient insulin secretion by pancreatic beta cells (Halban et al, 2014). T2D risk-associated variants are further enriched within large, contiguous regions of islet active chromatin, referred to as stretch or super-enhancers (Parker et al, 2013) These regions of active chromatin preferentially bind isletcell-restricted transcription factors and drive islet-specific gene expression (Parker et al, 2013; Pasquali et al, 2014). We identified T2D-associated variants localized in active enhancers in developmental precursors but not in mature islets, used genome editing in hESCs to define target genes of pancreatic progenitor-specific enhancers harboring T2D variants, and employed zebrafish genetic models to study the role of two target genes in pancreatic and endocrine cell development

Results

B Expression level of nearest expressed C genes to T2D risk-associated PSSE

Discussion

Materials and methods

Funding Funder National Institutes of Health