title: Tissue specific CTCF occupancy and boundary function at the human growth hormone locus.
abstract: The robust and tissue-specific activation of the human growth hormone (hGH) gene cluster in the pituitary and placenta constitutes an informative model for analysis of gene regulation. The five-gene hGH cluster is regulated by two partially overlapping sets of DNase I hypersensitive sites (HSs) that constitute the pituitary (HSI, II, III and V) and placental (HSIII, IV, and V) locus control regions (LCRs). The single placenta-specific LCR component, HSIV, is located at -30 kb to the cluster. Here we generate a series of hGH/BAC transgenes specifically modified to identify structural features of the hGH locus required for its appropriate placental expression. We find that placental specificity is dependent on the overall multigene configuration of the cluster whereas the distance between the cluster and its LCR impacts the level of placental expression. We further observe that a major function of the placental hGH LCR is to insulate the transgene locus from site-of-integration effects. This insulation activity is linked to placenta-specific occupancy of the chromatin architectural protein, CTCF, at HSIV. These data reveal a remarkable combination of structural configurations and regulatory determinants that must work in concert to insure robust and tightly controlled expression from a complex multigene locus.
authors.affiliation: Departments of Genetics and Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Tsai
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Cooke
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Liebhaber
mesh_terms: D000818:Animals; D000076246:CCCTC-Binding Factor; D003850:Deoxyribonuclease I; D005260:Female; D005786:Gene Expression Regulation; D056426:Genetic Loci; D019382:Human Growth Hormone / Q000235:genetics*; D006801:Humans; D038101:Insulator Elements; D019901:Locus Control Region; D051379:Mice; D008822:Mice, Transgenic; D005810:Multigene Family; D009928:Organ Specificity; D010920:Placenta / Q000378:metabolism; D010928:Placental Lactogen / Q000235:genetics*; D011247:Pregnancy; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; D012097:Repressor Proteins; D019382:Human Growth Hormone; D010928:Placental Lactogen; D003850:Deoxyribonuclease I