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PLoS Genet. 2014 Oct 16;10(10):e1004645. doi: 10.1371/journal.pgen.1004645. eCollection 2014 Oct.

An integrated cell purification and genomics strategy reveals multiple regulators of pancreas development.

Author information

1
Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America.
2
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, United States of America.
3
Institute for Cellular and Molecular Biology and Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, United States of America.
4
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, United States of America; Department of Dermatology, Stanford University School of Medicine,, Stanford, California, United States of America; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, United States of America.
5
Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, United States of America; Department of Medicine (Oncology Division), Stanford University School of Medicine, Stanford, California, United States of America.

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.

PMID:
25330008
PMCID:
PMC4199491
DOI:
10.1371/journal.pgen.1004645
[Indexed for MEDLINE]
Free PMC Article

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