title: An integrated cell purification and genomics strategy reveals multiple regulators of pancreas development.
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.
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Cecil M
authors.initials: CM
authors.lastname: Benitez
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Kun
authors.initials: K
authors.lastname: Qu
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Takuya
authors.initials: T
authors.lastname: Sugiyama
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Philip T
authors.initials: PT
authors.lastname: Pauerstein
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tsai
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Xueying
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Amar
authors.initials: A
authors.lastname: Ghodasara
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: H Efsun
authors.initials: HE
authors.lastname: Arda
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Jiajing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute for Cellular and Molecular Biology and Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Dekker
authors.affiliation: Institute for Cellular and Molecular Biology and Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Haley O
authors.initials: HO
authors.lastname: Tucker
authors.affiliation: 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.
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Seung K
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002469:Cell Separation / Q000379:methods*; D018507:Gene Expression Regulation, Developmental; D023281:Genomics / Q000379:methods; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D015233:Models, Statistical; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000166:cytology* / Q000196:embryology* / Q000254:growth & development*; D015203:Reproducibility of Results; D055758:SOX9 Transcription Factor / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D055758:SOX9 Transcription Factor; C407737:Neurog3 protein, mouse; C527933:Sox9 protein, mouse