Journal
PLOS GENETICS
Volume 10, Issue 10, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1004645
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Funding
- National Science Foundation
- U.S. NIH Developmental Genetics training grant
- HMMI
- Stanford MSTP
- NRSA from U.S. NIH
- JDRF
- NIH [CA-31534, P01-HG005062]
- Maria Betzner Morrow Endowment
- NIH Beta Cell Biology Consortium
- Early Career Scientist Award from the Howard Hughes Medical Institute (HHMI)
- Snyder Foundation
- Doolittle Charitable Trust
- Elser Foundation
- Helmsley Charitable Trust
- U.S. NIH Beta Cell Biology Consortium
- Howard Hughes Medical Institute (HHMI)
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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.
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