How do corepressors of nuclear hormone receptors control gene expression?

How do Corepressors of Nuclear Hormone Receptors Control Gene Expression?

Nuclear hormone receptors (NHRs) are a class of transcription factors that play a crucial role in regulating gene expression in response to hormonal signals. In order to achieve precise regulation, NHRs often require the assistance of corepressors, which are proteins that bind to the NHR and inhibit its activity. In this article, we will explore how corepressors of nuclear hormone receptors control gene expression.

Mechanisms of Corepressor Action

Corepressors of NHRs can exert their inhibitory effects through several mechanisms, including:

• Binding to the NHR: Corepressors can bind directly to the NHR, blocking its ability to bind to DNA and regulate gene expression. This binding can occur through specific protein-protein interactions, such as the interaction between the corepressor protein NCoR (nuclear receptor corepressor) and the NHR PXR (pregnane X receptor).
• Blocking coactivator binding: Corepressors can also prevent the binding of coactivators, which are proteins that enhance NHR activity, to the NHR. This is achieved by occupying the coactivator-binding site on the NHR, thereby preventing coactivator recruitment.
• Modifying NHR conformation: Corepressors can alter the conformation of the NHR, rendering it unable to bind to DNA or interact with coactivators. This can be achieved through post-translational modifications, such as phosphorylation or ubiquitination, which can alter the NHR’s structure and function.

Types of Corepressors

Several types of corepressors have been identified, including:

• NCoR: NCoR is a well-studied corepressor that interacts with multiple NHRs, including PXR, RXR (retinoid X receptor), and TR (thyroid hormone receptor).
• SMRT (silencing mediator for retinoid and thyroid receptors): SMRT is another corepressor that interacts with NHRs, including RXR and TR.
• HDACs (histone deacetylases): HDACs are enzymes that remove acetyl groups from histone proteins, leading to chromatin compaction and gene silencing. They can also act as corepressors by deacetylating NHRs and inhibiting their activity.

Regulation of Corepressor Activity

Corepressor activity can be regulated by various mechanisms, including:

• Hormone-dependent regulation: Corepressor activity can be influenced by the presence or absence of hormonal signals. For example, the corepressor NCoR can be phosphorylated and activated in response to hormonal signals, leading to increased repression of NHR-mediated gene expression.
• Post-translational modifications: Corepressor activity can also be regulated by post-translational modifications, such as ubiquitination or sumoylation, which can alter its binding affinity or activity.
• Interactions with other proteins: Corepressors can interact with other proteins, such as coactivators or other corepressors, to modulate their activity.

Disease Implications

Dysregulation of corepressor activity has been implicated in various diseases, including:

• Cancer: Corepressor dysregulation can contribute to tumorigenesis by altering NHR-mediated gene expression and promoting cell proliferation and survival.
• Metabolic disorders: Corepressor dysregulation can also contribute to metabolic disorders, such as diabetes and obesity, by altering NHR-mediated gene expression and insulin sensitivity.

Conclusion

In conclusion, corepressors of nuclear hormone receptors play a crucial role in regulating gene expression by inhibiting NHR activity. Through various mechanisms, including binding to the NHR, blocking coactivator binding, and modifying NHR conformation, corepressors can precisely regulate NHR-mediated gene expression. Understanding the mechanisms of corepressor action and regulation is essential for elucidating the role of NHRs in disease and developing therapeutic strategies to modulate NHR activity.

Table: Corepressors of Nuclear Hormone Receptors

References

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• 3. Chen, J. D., & Evans, R. M. (1995). A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature, 377(6545), 454-457.