title: Distinct chromatin configurations regulate the initiation and the maintenance of hGH gene expression.
abstract: For many mammalian genes, initiation of transcription during embryonic development must be subsequently sustained over extensive periods of adult life. It remains unclear whether maintenance of gene expression reflects the same set of pathways as are involved in initial gene activation. The human pituitary growth hormone (hGH-N) locus is activated in the differentiating somatotrope midway through embryogenesis by a multicomponent locus control region (LCR). DNase I-hypersensitive site I (HSI) of the LCR is essential to full developmental activation of the hGH-N locus. Here we demonstrate that conditional deletion of HSI from the active hGH locus in the adult pituitary effectively silences hGH-N expression. Analyses of chromatin structure and locus positioning demonstrate that a specific subset of the HSI functions active in the embryo retain their HSI dependence in the adult pituitary. These functions sustain engagement of the hGH locus with polymerase II (Pol II) factories, histone acetylation at the hGH-N promoter, and looping of the LCR to its target promoter. These data reveal that HSI is essential to both the maintenance and the initiation phases of gene expression. These observations contribute to our mechanistic understanding of how stable patterns of mammalian gene expression are established in a terminally differentiated cell.
authors: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. yho@mail.med.upenn.edu
authors: Yugong
authors: Y
authors: Ho
authors: Brian M
authors: BM
authors: Shewchuk
authors: Stephen A
authors: SA
authors: Liebhaber
authors: Nancy E
authors: NE
authors: Cooke
mesh_terms: D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D002843:Chromatin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004257:DNA Polymerase II / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D013006:Growth Hormone / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019901:Locus Control Region; D051379:Mice; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion; D050817:Transcription Factor Pit-1 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D019076:Transgenes
chemical_list: D002843:Chromatin; D050817:Transcription Factor Pit-1; D013006:Growth Hormone; D004257:DNA Polymerase II; D003850:Deoxyribonuclease I