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Transcriptional anti-repression. Thyroid hormone receptor beta-2 recruits SMRT corepressor but interferes with
Z Yang1, S H Hong, M L Privalsky
1Section of Microbiology, Division of Biological Sciences, University of California, Davis, California 95616, USA.
Abstract:
Thyroid hormone receptors (T3Rs) are hormone-regulated transcription factors. Different T3R isoforms are expressed in a tissue-specific and developmentally regulated manner. The T3Ralpha-1, beta-0, and beta-1 isoforms typically repress target gene expression in the absence of hormone and activate transcription in the presence of hormone. Intriguingly, however, the T3Rbeta-2 isoform fails to repress, and instead is able to activate transcription in both the absence and presence of hormone. We investigated the molecular mechanism behind this absence of repression by T3Rbeta-2. Repression by T3Ralpha-1, beta-0, and beta-1 is mediated by the ability of these isoforms to physically recruit a SMRT/N-CoR corepressor complex. We determined that the unliganded T3Rbeta-2 also recruits the SMRT corepressor; in contrast to the alpha-1, beta-0, and beta-1 isoforms, however, the T3Rbeta-2 protein interacts not only with the C-terminal "receptor-interaction domain" of SMRT, but also makes additional contacts with the N-terminal "silencing domain" of the SMRT corepressor. These additional, T3Rbeta-2-specific contacts interfere with the subsequent association of SMRT with mSin3, a crucial second subunit of the corepressor holo-complex. Our results suggest that T3Rbeta-2 regulates transcription through a novel anti-repression mechanism, recruiting SMRT, but preventing the subsequent formation of a functional corepressor complex.
Insights
Thyroid hormone receptor beta-2 (T3Rbeta-2) activates transcription without hormone by uniquely interacting with the SMRT corepressor, preventing functional complex formation and enabling anti-repression.
Area of Science:
- Molecular Endocrinology
- Gene Regulation
- Protein-Protein Interactions
Background:
- Thyroid hormone receptors (T3Rs) are transcription factors regulating gene expression.
- Different T3R isoforms exhibit distinct functions in gene regulation.
- T3Rbeta-2 uniquely activates transcription in both the absence and presence of thyroid hormone.
Purpose of the Study:
- To elucidate the molecular mechanism behind T3Rbeta-2's unique transcriptional activity.
- To understand why T3Rbeta-2 fails to repress target genes.
Main Methods:
- Investigated the interaction of T3Rbeta-2 with the SMRT/N-CoR corepressor complex.
- Analyzed protein-protein interactions using biochemical assays.
- Determined the specific binding domains involved in T3Rbeta-2 and SMRT interaction.
Main Results:
- Unliganded T3Rbeta-2 recruits the SMRT corepressor.
- T3Rbeta-2 interacts with both the C-terminal receptor-interaction domain and the N-terminal silencing domain of SMRT.
- These additional contacts block SMRT's association with the mSin3 subunit, inhibiting corepressor complex formation.
Conclusions:
- T3Rbeta-2 employs a novel anti-repression mechanism.
- It recruits SMRT but prevents the assembly of a functional corepressor holo-complex.
- This mechanism explains T3Rbeta-2's constitutive activation of transcription.