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Molecular and Cellular Biology, April 2004, p. 3337-3346, Vol. 24, No. 8
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.8.3337-3346.2004

Recruitment of N-CoR/SMRT-TBLR1 Corepressor Complex by Unliganded Thyroid Hormone Receptor for Gene Repression during Frog Development

Akihiro Tomita, Daniel R. Buchholz, and Yun-Bo Shi*

Section on Molecular Morphogenesis, Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-5431

Received 10 November 2003/ Returned for modification 9 December 2003/ Accepted 27 January 2004

The corepressors N-CoR (nuclear receptor corepressor) and SMRT (silencing mediator for retinoid and thyroid hormone receptors) interact with unliganded nuclear hormone receptors, including thyroid hormone (T3) receptor (TR). Several N-CoR/SMRT complexes containing histone deacetylases have been purified. The best studied among them are N-CoR/SMRT complexes containing TBL1 (transducin beta-like protein 1) or TBLR1 (TBL1-related protein). Despite extensive studies of these complexes, there has been no direct in vivo evidence for the interaction of TBL1 or TBLR1 with TR or the possible involvement of such complexes in gene repression by any nuclear receptors in any animals. Here, we used the frog oocyte system to demonstrate that unliganded TR interacts with TBLR1 and recruits TBLR1 to its chromatinized target promoter in vivo, accompanied by histone deacetylation and gene repression. We further provide evidence to show that the recruitment of TBLR1 or related proteins is important for repression by unliganded TR. To investigate the potential role for TBLR1 complexes during vertebrate development, we made use of T3-dependent amphibian metamorphosis as a model. We found that TBLR1, SMRT, and N-CoR are recruited to T3-inducible promoters in premetamorphic tadpoles and are released upon T3 treatment, which induces metamorphosis. More importantly, we demonstrate that the dissociation of N-CoR/SMRT-TBLR1 complexes from endogenous TR target promoters is correlated with the activation of these genes during spontaneous metamorphosis. Taken together, our studies provide in vivo evidence for targeted recruitment of N-CoR/SMRT-TBLR1 complexes by unliganded TR in transcriptional repression during vertebrate development.

* Corresponding author. Mailing address: Section on Molecular Morphogenesis, Laboratory of Gene Regulation and Development, NICHD/NIH, Building 18T, Room 106, Bethesda, MD 20892-5431. Phone: (301) 402-1004. Fax: (301) 402-1323. E-mail: shi{at}helix.nih.gov.

Molecular and Cellular Biology, April 2004, p. 3337-3346, Vol. 24, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.8.3337-3346.2004




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