한빛사 논문
Se Kyu Oha,1, Dongha Kima,1, Kyeongkyu Kima, Kyungjin Booa, Young Suk Yua, Ik Soo Kima, Yoon Jeonb, Sun-Kyoung Imc, Su-Hyung Leed, Ji Min Leee, Younhee Kof, Ho Leeb, Daechan Parkg,2, Sungsoon Fangc,2, and Sung Hee Baeka,2
a Creative Research Initiatives Center for Epigenetic Code and Diseases, School of Biological Sciences, Seoul National University, 08826 Seoul, South Korea; b Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, 10408 Goyang, South Korea; c Severance Biomedical Science Institute, BK21 Plus Project for Medical Science, Gangnam Severance Hospital, Yonsei University College of Medicine, 06273 Seoul, South Korea; d Branch of Carcinogenesis and Metastasis, Research Institute, National Cancer Center, 10408 Goyang, South Korea; e Department of Molecular Bioscience, College of Biomedical Sciences, Kangwon National University, 24341 Chuncheon, South Korea; f Division of Biomedical Engineering, Hankuk University of Foreign Studies, 17035 Yongin, South Korea; and g Department of Biological Sciences, College of Natural Sciences, Ajou University, 16499 Suwon, South Korea
1 S.K.O. and D.K. contributed equally to this work.
2 To whom correspondence may be addressed.
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).
epigenetic regulation, inflammation, RORα, HDAC3, NF-kB signaling
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