RORα is crucial for attenuated inflammatory response to maintain intestinal homeostasis

Abstract

Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, cancer, and metabolism. Here, we generate intestinal epithelial cell (IEC)-specific RORα-deficient (RORαΔIEC) mice and find that RORα is crucial for maintaining intestinal homeostasis by attenuating nuclear factor κB (NF-κB) transcriptional activity. RORαΔIEC mice exhibit excessive intestinal inflammation and highly activated inflammatory responses in the dextran sulfate sodium (DSS) mouse colitis model. Transcriptome analysis reveals that deletion of RORα leads to up-regulation of NF-κB target genes in IECs. Chromatin immunoprecipitation analysis reveals corecruitment of RORα and histone deacetylase 3 (HDAC3) on NF-κB target promoters and subsequent dismissal of CREB binding protein (CBP) and bromodomain-containing protein 4 (BRD4) for transcriptional repression. Together, we demonstrate that RORα/HDAC3-mediated attenuation of NF-κB signaling controls the balance of inflammatory responses, and therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of chronic inflammatory diseases, including inflammatory bowel disease (IBD).

RORα Regulates Cholesterol Metabolism of CD8+ T Cells for Anticancer Immunity

“…RORα specifically binds to PPARγ target promoter with HDAC3 for transcriptional regression of PPARγ [43]. It was also demonstrated that RORα controls the inflammatory signaling network, which is implicated in inflammatory bowel disease (IBD) [3]. The function of RORα was also shown in the regulation of T cells.…”

“…RORα acts as a checkpoint, specifically inhibiting NF-κB-mediated transcriptional activity in the cholesterol metabolism signaling pathway, which is essential for the activation of T cells ( Figure 5). Previously, our group found a correlation between RORα and HDAC3 in lipid homeostasis and genome-wide global promoter cooccupancy of RORα and NF-κB in intestinal epithelial cells [3,57]. However, connecting HDAC-RORα-NF-κB in activated T cells in the tumor microenvironment was the first approached; this connection is critical for crosstalk between cholesterol metabolism and the cytotoxicity of T cells.…”

“…RORα, a member of the orphan nuclear receptor (ONR) family, plays an essential role in various physiological functions such as cellular differentiation, metabolic pathway, inflammation, and cancer [1][2][3][4][5][6][7]. A recent study suggested that targeting the RORα downstream signaling of cholesterol metabolism modulates osteoarthritis pathogenesis [8], which indicates that the regulation of intracellular cholesterol levels is crucial for the pathogenesis of inflammation.…”

“…Further, RORα regulates the expression of Patterns recognition receptors (PRRs) upon the circadian rhythm [13]. Although the various functions of RORα as a negative regulator of the NF-κB signaling pathway have been shown [3,14], the molecular mechanisms associated with antitumor immunity remain to be determined.…”

Isoform-Specific Lysine Methylation of RORα2 by SETD7 Is Required for Association of the TIP60 Coactivator Complex in Prostate Cancer Progression

“…RORα binds as a monomer or homodimer to a specific DNA sequence known as the ROR response element (RORE) that consists of a 6-bp A/T-rich sequence preceding a half-site core motif PuGGTCA [6,7]. RORα was reported to regulate transcription of target genes through its interactions with many coactivators and corepressors, and it was shown to play important roles in many pathophysiological processes including circadian rhythm, development, the immune system, and metabolic homeostasis [5,[8][9][10][11]. Moreover, recent studies demonstrated that RORα is involved in tumorigenesis, suggesting that RORα may be considered a potential therapeutic target in many cancers [12][13][14][15].…”