| First Author | Oh SK | Year | 2019 |
| Journal | Proc Natl Acad Sci U S A | Volume | 116 |
| Issue | 42 | Pages | 21140-21149 |
| PubMed ID | 31570593 | Mgi Jnum | J:280409 |
| Mgi Id | MGI:6367683 | Doi | 10.1073/pnas.1907595116 |
| Citation | Oh SK, et al. (2019) RORalpha is crucial for attenuated inflammatory response to maintain intestinal homeostasis. Proc Natl Acad Sci U S A 116(42):21140-21149 |
| abstractText | Retinoic acid-related orphan receptor alpha (RORalpha) functions as a transcription factor for various biological processes, including circadian rhythm, cancer, and metabolism. Here, we generate intestinal epithelial cell (IEC)-specific RORalpha-deficient (RORalpha(DeltaIEC)) mice and find that RORalpha is crucial for maintaining intestinal homeostasis by attenuating nuclear factor kappaB (NF-kappaB) transcriptional activity. RORalpha(DeltaIEC) 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 RORalpha leads to up-regulation of NF-kappaB target genes in IECs. Chromatin immunoprecipitation analysis reveals corecruitment of RORalpha and histone deacetylase 3 (HDAC3) on NF-kappaB target promoters and subsequent dismissal of CREB binding protein (CBP) and bromodomain-containing protein 4 (BRD4) for transcriptional repression. Together, we demonstrate that RORalpha/HDAC3-mediated attenuation of NF-kappaB 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). |
