Page 4 - J. Chromatin remodeling and epigenetics

[J. Chromatin remodeling and epigenetics-2]

RORα is crucial for attenuated inflammatory response to

maintain intestinal homeostasis

Dongha Kim¹,#, Se Kyu Oh²,#, Daechan Park⁴,*, Sungsoon Fang³,*, Sung Hee Baek²,*

¹Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea, ²Creative

Research Initiatives Center for Epigenetic Code and Diseases, School of Biological Sciences, Seoul National
University, Seoul 08826, Korea, ³Severance Biomedical Science Institute, Yonsei University College of Medicine,

Seoul 06273, Korea, ⁴Biological Sciences, Ajou University, Suwon 16499, Korea

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 bromodomaincontaining 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).