Liver X receptors interact with corepressors to regulate gene expression

Area of Science:

• Molecular Biology
• Endocrinology
• Genetics

Background:

• Liver X receptors (LXRs) are nuclear receptors crucial for cholesterol homeostasis and gene regulation.
• LXRs activate transcription via coactivator recruitment upon binding oxysterols or synthetic agonists.
• The function of LXRs in the absence of ligands was previously unknown.

Purpose of the Study:

• To investigate the role of LXRs in regulating target gene expression in the absence of ligand.
• To determine if LXRs interact with corepressors and if this interaction is ligand-dependent.

Main Methods:

• Transient transfection assays were used to assess LXR-mediated transcriptional regulation.
• Interaction studies identified corepressors N-CoR and SMRT binding to LXRs.
• Chromatin immunoprecipitation (ChIP) experiments examined corepressor recruitment to endogenous LXR target genes.

Main Results:

• LXRs interact with corepressors N-CoR and SMRT, which are released upon agonist binding.
• LXRalpha shows a strong interaction with corepressors, while LXRbeta exhibits a weak interaction.
• N-CoR is recruited to endogenous LXR target genes and released by LXR agonists, demonstrating ligand-dependent repression.

Conclusions:

• Corepressors play a significant role in the basal repression of LXR target genes.
• The interaction between LXRs and corepressors is isoform-selective and ligand-dependent.
• These findings reveal a novel mechanism for LXR-mediated gene regulation involving corepressor release.