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

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.

Sequence logic at enhancers governs a dual mechanism of endodermal organ fate induction by FOXA pioneer factors

“…Hi-C data analysis. Hi-C data were processed as previously described 63 . Read pairs were aligned to the hg19 reference genome separately using BWA-MEM with default parameters 53 .…”

Regulatory variants active in iPSC-derived pancreatic progenitor cells are associated with Type 2 Diabetes in adults

“…Here, we showed that characterizing the functional effects of individual SNPs using TOBIAS (Bentsen et al, 2020), deltaSVM predictions (Ghandi et al, 2014; Ghandi et al, 2016; Yan et al, 2021) or ASE, provides an alternative method to pinpoint the likely causal SNPs and may help discriminate neutral SNPs that are in high LD. Although the analyses proposed here identified SNPs that are associated with the active regulatory elements in iPSC-PPC, further analyses that integrate the results presented here with co-accessibility, expression quantitative trait loci (eQTLs) (Vinuela et al, 2020), chromatin accessibility QTLs (Alasoo et al, 2018), colocalization between QTLs and GWAS (Giambartolomei et al, 2014; Giambartolomei et al, 2018; Majumdar et al, 2018; Wallace, 2020) and, ultimately, experimental validation (Geusz et al, 2020), are needed to link their effects with their target genes and thus, functional mechanisms, as most regulatory elements are not in close proximity to promoters, and distal regulatory elements may regulate multiple genes (Oh et al, 2021). By empowering chromatin accessibility profiles with advanced tools such as transcription factor footprinting, allelic effect predictions, and co-accessibility, it is feasible to uncover novel molecular mechanisms that underlie the genetic risk of T2D.…”

“…Although several studies have successfully identified the likely causal variant in a small subset of T2D- associated loci (Chiou et al, 2021; Mahajan et al, 2018; Varshney et al, 2017), the vast majority of the signals still remains uncharacterized and typically lie within regulatory regions. Given the importance of many transcription factors in regulating pancreatic cells’ function, it is not surprising that many non-coding validated T2D risk variants overlap transcription factor binding sites (Chiou et al, 2021; Geusz et al, 2020; Greenwald et al, 2019; Mahajan et al, 2018; Rai et al, 2020; Thurner et al, 2018), indicating that snATAC-seq provides an optimal method to identify the molecular mechanisms underlying the role of regulatory variants in this disease.…”

Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction

“…Another study performed scRNA-seq during all the steps of differentiation of hESCs toward β cells, generating a transcriptomic atlas of SC-β differentiation and paying special attention to the enrichment of genes linked to T2D-GWAS [ 235 ]. Epigenomic maps consisting of chromatin accessibility, histone marks and 3D chromatin architecture from hESC-derived progenitors, at multiple steps are also recently available [ 237 , 238 ].…”

“…Genome-wide survey of open chromatin accessibility by DNase-seq, ATAC-seq and histone modification ChIP-seq has identified unique regulatory elements that reveal tissue-specific features [ 272 , 287 ]. Studies integrated with T2D-GWAS found risk signals enriched at enhancers active in islets [ 72 , 230 , 288 , 289 ] or in hESC-derived progenitors [ 237 ]. Several studies have attributed gene expression effects and diabetes-GWAS signals to causal SNPs in enhancer regions.…”