title: An autoregulatory pathway establishes the definitive chromatin conformation at the pit-1 locus.
abstract: The transcription factor Pit-1 (POU1-F1) plays a dominant role in cell lineage expansion and differentiation in the anterior pituitary. Prior studies of the mouse Pit-1 (mPit-1) gene revealed that this master regulatory locus is activated at embryonic day 13.5 (E13.5) by an early enhancer (EE), whereas its subsequent expression throughout adult life is maintained by a more distal definitive enhancer (DE). Here, we demonstrate that the sequential actions of these two enhancers are linked to corresponding shifts in their proximities to the Pit-1 promoter. We further demonstrate that the looping of the definitive enhancer to the mPit-1 promoter is critically dependent on a self-sustaining autoregulatory mechanism mediated by the Pit-1 protein. These Pit-1-dependent actions are accompanied by localized recruitment of CBP and enrichment for H3K27 acetylation within the Pit-1 locus. These data support a model in which the sequential actions of two developmentally activated enhancers are linked to a corresponding shift in higher-order chromatin structures. This shift establishes an autoregulatory circuit that maintains durable expression of Pit-1 throughout adult life.
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA yho@mail.med.upenn.edu.
authors.forename: Yugong
authors.initials: Y
authors.lastname: Ho
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Cooke
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Liebhaber
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D006657:Histones / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D050817:Transcription Factor Pit-1 / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D002843:Chromatin; D006657:Histones; D050817:Transcription Factor Pit-1