RORα is crucial for attenuated inflammatory response to maintain intestinal homeostasis

Area of Science:

• Molecular Biology
• Immunology
• Gastroenterology

Background:

• Retinoic acid-related orphan receptor alpha (RORα) is a transcription factor involved in diverse biological processes.
• Intestinal homeostasis and inflammation are critical areas of research with significant clinical implications.

Purpose of the Study:

• To investigate the role of RORα in intestinal epithelial cells (IECs) in maintaining intestinal homeostasis.
• To elucidate the molecular mechanisms by which RORα regulates inflammation, particularly NF-κB signaling.

Main Methods:

• Generation of intestinal epithelial cell-specific RORα-deficient (RORα^ΔIEC) mice.
• Dextran sulfate sodium (DSS)-induced mouse colitis model to assess inflammation.
• Transcriptome analysis to identify gene expression changes.
• Chromatin immunoprecipitation (ChIP) assays to study protein-DNA interactions.

Main Results:

• RORα^ΔIEC mice exhibited exacerbated intestinal inflammation and heightened inflammatory responses in the DSS colitis model.
• Deletion of RORα led to significant upregulation of NF-κB target genes in IECs.
• RORα and HDAC3 were found to be corecruited to NF-κB target promoters, leading to the dismissal of CBP and BRD4, thereby repressing transcription.

Conclusions:

• RORα plays a crucial role in maintaining intestinal homeostasis by attenuating NF-κB transcriptional activity.
• The RORα/HDAC3 complex epigenetically represses NF-κB signaling, controlling inflammatory responses.
• Targeting this RORα/HDAC3-mediated epigenetic regulation presents a potential therapeutic strategy for chronic inflammatory diseases like inflammatory bowel disease (IBD).