title: Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A.
abstract: Maintenance of cell type identity is crucial for health, yet little is known of the regulation that sustains the long-term stability of differentiated phenotypes. To investigate the roles that key transcriptional regulators play in adult differentiated cells, we examined the effects of depletion of the developmental master regulator PTF1A on the specialized phenotype of the adult pancreatic acinar cell in vivo Transcriptome sequencing and chromatin immunoprecipitation sequencing results showed that PTF1A maintains the expression of genes for all cellular processes dedicated to the production of the secretory digestive enzymes, a highly attuned surveillance of unfolded proteins, and a heightened unfolded protein response (UPR). Control by PTF1A is direct on target genes and indirect through a ten-member transcription factor network. Depletion of PTF1A causes an imbalance that overwhelms the UPR, induces cellular injury, and provokes acinar metaplasia. Compromised cellular identity occurs by derepression of characteristic stomach genes, some of which are also associated with pancreatic ductal cells. The loss of acinar cell homeostasis, differentiation, and identity is directly relevant to the pathologies of pancreatitis and pancreatic adenocarcinoma.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Chinh Q
authors.initials: CQ
authors.lastname: Hoang
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hale
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Azevedo-Pouly
authors.affiliation: Department of Cytobiology, Philipps University of Marburg, Marburg, Germany.
authors.forename: Hans P
authors.initials: HP
authors.lastname: Elsässer
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Tye G
authors.initials: TG
authors.lastname: Deering
authors.affiliation: Program in Developmental Biology and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Spencer G
authors.initials: SG
authors.lastname: Willet
authors.affiliation: Program in Developmental Biology and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Fong C
authors.initials: FC
authors.lastname: Pan
authors.affiliation: Department of Molecular Physiology and Biophysics and Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Mark A
authors.identifier: 0000-0002-8824-6499
authors.initials: MA
authors.lastname: Magnuson
authors.affiliation: Program in Developmental Biology and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Christopher V E
authors.initials: CV
authors.lastname: Wright
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Galvin H
authors.initials: GH
authors.lastname: Swift
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA raymond.macdonald@utsouthwestern.edu.
authors.forename: Raymond J
authors.identifier: 0000-0002-8576-766X
authors.initials: RJ
authors.lastname: MacDonald
mesh_terms: D061354:Acinar Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006706:Homeostasis; D051379:Mice; D046790:Pancreas, Exocrine / Q000166:cytology* / Q000378:metabolism; D058767:Protein Unfolding; D017423:Sequence Analysis, RNA / Q000379:methods; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D056811:Unfolded Protein Response
chemical_list: D014157:Transcription Factors; C062602:transcription factor PTF1