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Negative Regulation of TSH Target Gene by Thyroid Hormone Involves Histone Acetylation and Corepressor Complex Dissociation

Endocrinology Division (D.W., X.X., P.M.Y.), Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224; Department of Pharmacology (P.A.C.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Developmental Endocrinology Branch (Y.L.), and Laboratory of Gene Regulation and Development (A.O., Y.-B.S.), National Institutes of Child Health and Human Development, National Institutes of Health and Genetics Branch (R.L.W., Y.Z., P.M.), National Cancer Institute, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Paul M. Yen, M.D., Cardiovascular and Metabolism Program, Duke-NUS Graduate Medical School, 2 Jalan Bukit Merah, Singapore 169547. E-mail: paul.yen{at}duke-nus.edu.sg.

Currently, little is known about histone modifications and molecular mechanisms of negatively regulated transcription. In pituitary cells, thyroid hormone (T₃) decreased transcription, and surprisingly increased histone acetylation, of TSH 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 TSH promoter. T₃ also caused release of a corepressor complex composed of histone deacetylase 3 (HDAC3), transducin β-like protein 1, and nuclear receptor coprepressor (NCoR)/ silencing mediator for retinoic and thyroid hormone receptor from TSH 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 T₃. Chromatin immunoprecipitation analyses of an endogenous positively regulated target gene showed increased histone acetylation and corepressor complex release with T₃ 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 TSH gene expression and show that similar complexes and overlapping epigenetic modifications can participate in both negative and positive transcriptional regulation.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα

Coregulators:   TBL1  |  HDAC3  |  NCOR  |  SMRT

Ligands:   Thyroid hormone