Abstract
The regulatory logic underlying global transcriptional programs controlling development of visceral organs like the pancreas remains undiscovered. Here, we profiled gene expression in 12 purified populations of fetal and adult pancreatic epithelial cells representing crucial progenitor cell subsets, and their endocrine or exocrine progeny. Using probabilistic models to decode the general programs organizing gene expression, we identified co-expressed gene sets in cell subsets that revealed patterns and processes governing progenitor cell development, lineage specification, and endocrine cell maturation. Purification of Neurog3 mutant cells and module network analysis linked established regulators such as Neurog3 to unrecognized gene targets and roles in pancreas development. Iterative module network analysis nominated and prioritized transcriptional regulators, including diabetes risk genes. Functional validation of a subset of candidate regulators with corresponding mutant mice revealed that the transcription factors Etv1, Prdm16, Runx1t1 and Bcl11a are essential for pancreas development. Our integrated approach provides a unique framework for identifying regulatory genes and functional gene sets underlying pancreas development and associated diseases such as diabetes mellitus.
Highlights
The pancreas is a vital internal organ with exocrine and endocrine functions
Discovery of specific pancreas developmental regulators has accelerated in recent years
Our work revealed regulatory gene sets governing development of pancreas progenitor cells and their progeny
Summary
The pancreas is a vital internal organ with exocrine and endocrine functions. The exocrine pancreas is composed of acinar cells that secrete digestive enzymes into a branched network of bicarbonate-secreting duct cells. Classical genetic approaches revealed that exocrine and endocrine cells develop from a common multipotent progenitor that expresses the transcription factors Sox9 [2] [3], Pdx1 [4], and Ptf1a [5]. Sox9+ multipotent progenitors generate endocrine progenitors that express the basic helix-loop-helix (bHLH) transcription factor Neurog3 [6], which produce all pancreatic endocrine cells [7]. These approaches have revealed much about individual factors that regulate pancreatic development [8], we have yet to understand the regulatory logic underlying pancreas formation [9]
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