eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk

Abstract

Pancreatic progenitor cells (PPCs), which are multipotent cells that have the potential to give rise to endocrine, exocrine and epithelial cells, provide a powerful model system to examine the molecular characteristics of differentiating, fetal-like pancreas cells and to study the genetics of pancreatic disease. We differentiated ten induced pluripotent stem cell-derived pancreatic progenitor cell (iPSC-PPC) lines and, using single cell RNA-seq and single nuclear ATAC-seq, we found that they show varying levels of cellular maturity, including the presence of early PPC, endocrine and exocrine cells. We evaluated iPSC-PPC as a model system to study type 2 diabetes (T2D) and found that, of 380 T2D risk loci, 208 overlapped regulatory elements active in iPSC-PPC, including 55 fetal-specific. These loci are associated with transcription factor binding site alterations and allele-specific expression, suggesting that iPSC-PPC are an optimal model system to annotate GWAS variants that are not functional in the adult pancreas.

Limited overlap of eQTLs and GWAS hits due to systematic differences in discovery

“…Multiple potential explanations have been proposed for the limited overlap between GWAS hits and eQTLs. One is that some GWAS hits may only be eQTLs in specific contexts, e.g., during development [16,[19][20][21][22], in specific cell types [23][24][25][26], or in response to physiological stimuli such as immune responses [27][28][29][30][31]. These effects are expected to be absent, or hard to detect, in conventional eQTL assays using post-mortem adult whole tissues.…”

Single-cell profiling of GP2-enriched pancreatic progenitors to simultaneously create acinar, ductal, and endocrine organoids

“…Using GO term analysis and GSEA, we determined the identity as acinar-directed (progenytors 1), progenitor-like (progenitors 2) and ductal progenitor (progenitors 3). Hence, the entire pancreatic progenitor population therefore appeared to be heterogenous, harboring different cell types that are already primed for their respective cell lineage fates, exhibiting different degrees of maturity due to asynchronous differentiation 32 .…”

“…Moreover, even the expression level of NKX6-1 per se determines subsequent lineage potential 12 , 31 . Most recently, a preprinted study performed large-scale single cell transcriptomics for a number of human pluripotent stem cell (hPSC)-derived PPs and found pancreatic cell types at varying levels of maturity due to asynchronous differentiation accounting for a large fraction of the PP heterogeneity 32 . Thus, well-defined and trilineage competent PPs are critical to truthfully mimic human fetal pancreatogenesis and to study pancreatic diseases, such as diabetes or pancreatic cancer.…”

Analysis of regulatory network modules in hundreds of human stem cell lines reveals complex epigenetic and genetic factors contribute to pluripotency state differences between subpopulations

“…In addition to heritable, complex diseases that have known developmental origins (i.e. autism spectrum disorder, schizophrenia), there is mounting evidence that common diseases, such as type 2 diabetes 65 and cardiovascular disease 18 , are influenced by regulatory variation that is active during fetal development. It is paramount to expand exploration into these areas of research to characterize developmental regulatory variation.…”