title: Negative regulation of TSHalpha target gene by thyroid hormone involves histone acetylation and corepressor complex dissociation.
abstract: Currently, little is known about histone modifications and molecular mechanisms of negatively regulated transcription. In pituitary cells, thyroid hormone (T(3)) decreased transcription, and surprisingly increased histone acetylation, of TSHalpha promoter. This increase was mediated directly by thyroid hormone receptor. Histone acetylation of H3K9 and H3K18 sites, two modifications usually associated with transcriptional activation, occur in negative regulation of TSHalpha promoter. T(3) also caused release of a corepressor complex composed of histone deacetylase 3 (HDAC3), transducin beta-like protein 1, and nuclear receptor coprepressor (NCoR)/ silencing mediator for retinoic and thyroid hormone receptor from TSHalpha promoter in chromatin immunoprecipitation assays. NCoR and HDAC3 overexpression selectively increased ligand-independent basal transcription. Two histone acetyltransferase inhibitors increased overall transcription but did not abrogate negative regulation or NCoR/HDAC3 complex release by T(3). Chromatin immunoprecipitation analyses of an endogenous positively regulated target gene showed increased histone acetylation and corepressor complex release with T(3) treatment. Finally, microarray analyses suggested there is a subset of negatively regulated genes with increased histone acetylation. These findings demonstrate the critical role of NCoR/HDAC3 complex in negative regulation of TSHalpha gene expression and show that similar complexes and overlapping epigenetic modifications can participate in both negative and positive transcriptional regulation.
authors.affiliation: Endocrinology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Wang
authors.forename: Xianmin
authors.initials: X
authors.lastname: Xia
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Alexis
authors.initials: A
authors.lastname: Oetting
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walker
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Zhu
authors.forename: Paul
authors.initials: P
authors.lastname: Meltzer
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
authors.forename: Yun-Bo
authors.initials: YB
authors.lastname: Shi
authors.forename: Paul M
authors.initials: PM
authors.lastname: Yen
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation / Q000187:drug effects*; D015292:Glycoprotein Hormones, alpha Subunit / Q000235:genetics*; D006657:Histones / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015293:Transducin / Q000378:metabolism; D014284:Triiodothyronine / Q000494:pharmacology*
chemical_list: D015292:Glycoprotein Hormones, alpha Subunit; D006657:Histones; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D014284:Triiodothyronine; D015293:Transducin