title: MIST1 and PTF1 Collaborate in Feed-Forward Regulatory Loops That Maintain the Pancreatic Acinar Phenotype in Adult Mice.
abstract: Much remains unknown regarding the regulatory networks formed by transcription factors in mature, differentiated mammalian cellsin vivo, despite many studies of individual DNA-binding transcription factors. We report a constellation of feed-forward loops formed by the pancreatic transcription factors MIST1 and PTF1 that govern the differentiated phenotype of the adult pancreatic acinar cell. PTF1 is an atypical basic helix-loop-helix transcription factor complex of pancreatic acinar cells and is critical to acinar cell fate specification and differentiation. MIST1, also a basic helix-loop-helix transcription factor, enhances the formation and maintenance of the specialized phenotype of professional secretory cells. The MIST1 and PTF1 collaboration controls a wide range of specialized cellular processes, including secretory protein synthesis and processing, exocytosis, and homeostasis of the endoplasmic reticulum. PTF1 drivesMist1transcription, and MIST1 and PTF1 bind and drive the transcription of over 100 downstream acinar genes. PTF1 binds two canonical bipartite sites within a 0.7-kb transcriptional enhancer upstream ofMist1that are essential for the activity of the enhancerin vivoMIST1 and PTF1 coregulate target genes synergistically or additively, depending on the target transcriptional enhancer. The frequent close binding proximity of PTF1 and MIST1 in pancreatic acinar cell chromatin implies extensive collaboration although the collaboration is not dependent on a stable physical interaction.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Jiang
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 Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Tye G
authors.initials: TG
authors.lastname: Deering
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 Biological Sciences, Bindley Bioscience Center and Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: DiRenzo
authors.affiliation: Department of Biological Sciences, Bindley Bioscience Center and Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Hess
authors.affiliation: Department of Biological Sciences, Bindley Bioscience Center and Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Stephen F
authors.identifier: http://orcid.org/0000-0002-3281-3714
authors.initials: SF
authors.lastname: Konieczny
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: http://orcid.org/0000-0002-8576-766X
authors.initials: RJ
authors.lastname: MacDonald