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The nuclear corepressors recognize distinct nuclear receptor complexes
R N Cohen1, A Putney, F E Wondisford
1Department of Medicine, Beth Israel Deaconess Medical Center and Harvard, Boston, Massachusetts 02215, USA.
Abstract:
The thyroid hormone receptor (TR) and retinoic acid receptor (RAR) isoforms have the capacity to silence gene expression in the absence of their ligands on target response elements. This active repression is mediated by the ability of the corepressors, nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid hormone receptors (SMRT), to recruit a complex containing histone deacetylase activity. Interestingly, NCoR and SMRT share significant differences in the their two nuclear receptor-interacting domains (IDs), suggesting that they may recruit receptors with different affinities. In addition, the role of the receptor complex bound to a response element has not been fully evaluated in its ability to recruit separate corepressors. We demonstrate in this report that the proximal ID in NCoR and SMRT, which share only 23% homology, allows preferential recognition of nuclear receptors, such that TR prefers to recruit NCoR, and RAR prefers to recruit SMRT, to DNA response elements. However, mutations in the TR found in the syndromes of resistance to thyroid hormone can change the corepressor recruited by changing the complex (homodimer or heterodimer) formed on the TRE. These results demonstrate that the corepressor complex recruited can be both nuclear receptor- and receptor complex-specific.
Insights
Thyroid hormone receptor (TR) and retinoic acid receptor (RAR) preferentially recruit specific corepressors (NCoR and SMRT) via distinct interaction domains. Receptor complex formation on DNA response elements further influences corepressor recruitment specificity.
Area of Science:
- Molecular Endocrinology
- Gene Regulation
- Nuclear Receptor Signaling
Background:
- Thyroid hormone receptor (TR) and retinoic acid receptor (RAR) are nuclear receptors that repress gene expression without ligands.
- This repression involves corepressors nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid hormone receptors (SMRT), which recruit histone deacetylase activity.
- NCoR and SMRT possess distinct nuclear receptor-interacting domains (IDs), suggesting differential receptor binding affinities.
Purpose of the Study:
- To investigate the specificity of NCoR and SMRT corepressor recruitment by TR and RAR.
- To determine how receptor complex formation on DNA response elements affects corepressor selection.
- To elucidate the role of proximal IDs in NCoR and SMRT for nuclear receptor recognition.
Main Methods:
- Comparative analysis of NCoR and SMRT proximal ID homology.
- Assessing corepressor recruitment by TR and RAR to DNA response elements.
- Evaluating the impact of TR mutations and different receptor complex formations (homodimers, heterodimers) on corepressor binding.
Main Results:
- The proximal IDs of NCoR and SMRT, despite low homology, mediate preferential corepressor recruitment.
- TR specifically prefers NCoR, while RAR preferentially recruits SMRT to DNA response elements.
- Mutations in TR associated with resistance to thyroid hormone alter corepressor recruitment by changing the receptor complex composition on the TRE.
Conclusions:
- Corepressor complex recruitment is specific to both the nuclear receptor type and the receptor complex assembled on DNA.
- Understanding these specificities is crucial for deciphering gene silencing mechanisms regulated by nuclear receptors.
- This provides insights into the molecular basis of resistance to thyroid hormone syndromes.