title: Cell type-dependent recruitment of trichostatin A-sensitive repression of the human 5-HT1A receptor gene.
abstract: Regulation of serotonin (5-HT)1A receptor expression in brain is implicated in mood disorders such as depression and anxiety. Transcriptional activity of the human 5-HT1A receptor gene was strongly repressed by a negative regulatory region containing a consensus repressor element-1 (RE-1) and two copies of the dual repressor element (DRE) identified in the rat 5-HT1A receptor gene. REST/NRSF, a silencer of neuronal genes, bound the 5-HT1A RE-1 and repressed the 5-HT1A promoter. Inactivation of RE-1 completely abolished REST-mediated repression, but resulted in only partial (15-50%) de-repression of basal 5-HT1A promoter activity. The human 5-HT1A DRE sequences bound specifically to the novel repressor Freud-1 (5'repressor element under dual repression binding protein-1) and conferred repressor activity at 5-HT1A or SV40 promoters. In 5-HT1A-negative cells [L6, human embryonic kidney (HEK) 293], the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) abolished repression mediated by both RE-1/REST and DRE/Freud-1, and induced almost complete de-repression of the 5-HT1A gene. By contrast, in 5-HT1A-expressing neuronal cells (RN46A, SN-48) TSA blocked RE-1/REST repression, but did not affect DRE/Freud-1-mediated repression. Thus in contrast to REST, Freud-1 mediates HDAC-independent repression of the 5-HT1A receptor promoter in neuronal 5-HT1A-positive cells, suggesting that HDAC recruitment might influence neuron-specific gene expression by further silencing expression in non-neuronal tissue.
authors.affiliation: Ottawa Health Research Institute, Departments of Medicine and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lemonde
authors.forename: Anastasia
authors.initials: A
authors.lastname: Rogaeva
authors.forename: Paul R
authors.initials: PR
authors.lastname: Albert
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins; D002460:Cell Line; D003001:Cloning, Molecular / Q000379:methods; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004622:Embryo, Mammalian; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney; D008156:Luciferases / Q000378:metabolism; D008969:Molecular Sequence Data; D032446:Myoblasts / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D001616:beta-Galactosidase / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D002352:Carrier Proteins; D006877:Hydroxamic Acids; D008156:Luciferases; D011500:Protein Synthesis Inhibitors; D044282:Receptor, Serotonin, 5-HT1A; D012097:Repressor Proteins; D014157:Transcription Factors; D001616:beta-Galactosidase; D000099229:RE1-Silencing Transcription Factor; C012589:trichostatin A