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Thyroid hormone receptor coactivators and corepressors
1Division of Endocrinology, University of Michigan Medical Center, Ann Arbor 48109-0678, USA.
Abstract:
In the absence of triiodothyronine (T3), thyroid hormone receptors (TRs) repress transcription of many genes; in the presence of T3, TRs activate transcription of those same genes. Both of these events are dependent on interactions between TRs and other nuclear proteins. TRs bind to specific DNA sequences, generally found in the 5' flanking regions of target genes. In the unliganded state, TRs interact with one of several corepressor proteins. These proteins, in turn, interact with a series of other proteins, which includes histone deacetylases. Histone deacetylation tightens chromatin structure, thus impairing access of critical transcription factors and thereby repressing transcription. In addition, corepressors may invoke mechanisms of gene repression independent of histone deacetylation. The binding of T3 causes a conformational change in the TR that results in release of the corepressor and recruitment of coactivator proteins. Several coactivator proteins appear to bind the ligand-occupied TR as a multiprotein complex. Opposite to corepressors, coactivators acetylate histones, thereby loosening chromatin structure and facilitating access of key transcription factors. Again, mechanisms independent of histone acetylation also may be involved. Overall, gene activation by T3 is a two-step process; removal of active repression, and induction of transcription to levels above the "neutral" state.
Insights
Thyroid hormone receptors (TRs) regulate gene transcription by interacting with corepressors or coactivators. Triiodothyronine (T3) binding to TRs shifts this interaction, activating gene expression through chromatin remodeling.
Area of Science:
- Molecular Biology
- Endocrinology
- Genetics
Background:
- Thyroid hormone receptors (TRs) bind DNA and regulate gene transcription.
- TRs interact with nuclear proteins to modulate gene expression.
- Gene regulation by TRs is dependent on the presence or absence of triiodothyronine (T3).
Purpose of the Study:
- To elucidate the molecular mechanisms by which TRs regulate gene transcription.
- To understand the role of corepressors and coactivators in T3-mediated gene regulation.
- To detail the process of gene activation by T3.
Main Methods:
- Analysis of protein-DNA interactions.
- Investigation of protein-protein interactions.
- Study of chromatin remodeling via histone acetylation and deacetylation.
Main Results:
- Unliganded TRs recruit corepressors, leading to histone deacetylation and gene repression.
- T3 binding induces a conformational change in TRs, releasing corepressors and recruiting coactivators.
- Coactivators facilitate gene activation through histone acetylation and other mechanisms.
Conclusions:
- T3-mediated gene activation involves a two-step process: removal of repression and induction of transcription.
- TRs act as molecular switches, integrating signals from T3 to control gene expression.
- Chromatin modification is a key mechanism in thyroid hormone-regulated gene transcription.