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Molecular and Cellular Biology, August 2003, p. 5122-5131, Vol. 23, No. 15
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.15.5122-5131.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The N-CoR/Histone Deacetylase 3 Complex Is Required for Repression by Thyroid Hormone Receptor

Takahiro Ishizuka and Mitchell A. Lazar*

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and Department of Genetics and The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Received 13 March 2003/ Returned for modification 15 April 2003/ Accepted 15 May 2003

Nuclear receptor corepressors (N-CoR) and silencing mediator for retinoid and thyroid receptors (SMRT) have both been implicated in thyroid hormone receptor (TR)-mediated repression. Here we show that endogenous N-CoR, TBL1, and histone deacetylase 3 (HDAC3), but not HDAC1, -2, or -4, are recruited to a stably integrated reporter gene repressed by unliganded TR as well as the orphan receptor RevErb. Unliganded TR also recruits this complex to a transiently transfected reporter, and transcriptional repression is associated with local histone deacetylation that is reversed by the presence of thyroid hormone. Knockdown of N-CoR using small interfering RNAs markedly reduces repression by the TR ligand binding domain in human 293T cells, whereas knockdown of SMRT has little effect. RevErb repression appears to involve both corepressors in this system. Knockdown of HDAC3 markedly reduces repression by both TR and RevErb, while knockdown of HDAC1 or 2 has more modest, partly nonspecific effects. Thus, HDAC3 is critical for repression by multiple nuclear receptors and the N-CoR HDAC3 complex plays a unique and necessary role in TR-mediated gene repression in human 293T cells.

* Corresponding author. Mailing address: University of Pennsylvania School of Medicine, 611 CRB, 415 Curie Blvd., Philadelphia, PA 19104-6149. Phone: (215) 898-0198. Fax: (215) 898-5408. E-mail: lazar{at}mail.med.upenn.edu.

Molecular and Cellular Biology, August 2003, p. 5122-5131, Vol. 23, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.15.5122-5131.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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