RORα is crucial for attenuated inflammatory response to maintain intestinal homeostasis

Se Kyu Oh, Dongha Kim, Kyeongkyu Kim, Kyungjin Boo, Young Suk Yu, Ik Soo Kim, Yoon Jeon, Sun-Kyoung Im, Su-Hyung Lee, Ji Min Lee, Younhee Ko, Ho Lee, Daechan Park, Sungsoon Fang, and Sung Hee Baek
PNAS October 15, 2019 116 (42) 21140-21149; first published September 30, 2019 https://doi.org/10.1073/pnas.1907595116

  1. Edited by David D. Moore, Baylor College of Medicine, Houston, TX, and approved September 12, 2019 (received for review May 3, 2019)

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

Significance

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, and the worldwide prevalence of IBD rapidly continues to rise. It has been widely accepted that genetic predisposition remains an important risk factor of IBD in addition to microbiota, dietary environment, and immune response. In this study, we demonstrated that retinoic acid-related orphan receptor α (RORα) controls the inflammatory signaling network to maintain homeostasis in vivo in intestinal epithelium. Our study strongly proposes that RORα is a therapeutic target for the treatment of IBD.

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).

Footnotes

  • ↵1S.K.O. and D.K. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: dpark{at}ajou.ac.kr, sfang{at}yuhs.ac.kr, or sbaek{at}snu.ac.kr.

  • Author contributions: S.K.O., D.K., K.K., I.S.K., J.M.L., and S.H.B. designed research; S.K.O., D.K., K.K., S.-K.I., and S.F. performed research; S.K.O., K.K., K.B., Y.J., and H.L. contributed new reagents/analytic tools; S.K.O., D.K., K.K., Y.S.Y., S.-H.L., Y.K., D.P., and S.F. analyzed data; and S.K.O., D.K., D.P., S.F., and S.H.B. wrote the paper.

  • The authors declare no competing interest.

  • This article is a PNAS Direct Submission.

  • Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE121977).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1907595116/-/DCSupplemental.

Published under the PNAS license.

View Full Text

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
Back to top
Article Alerts
Email Article
Citation Tools
Request Permissions
RORα is crucial for attenuated inflammatory response to maintain intestinal homeostasis
Se Kyu Oh, Dongha Kim, Kyeongkyu Kim, Kyungjin Boo, Young Suk Yu, Ik Soo Kim, Yoon Jeon, Sun-Kyoung Im, Su-Hyung Lee, Ji Min Lee, Younhee Ko, Ho Lee, Daechan Park, Sungsoon Fang, Sung Hee Baek
Proceedings of the National Academy of Sciences Oct 2019, 116 (42) 21140-21149; DOI: 10.1073/pnas.1907595116
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Proceedings of the National Academy of Sciences: 116 (47)
Current Issue

Submit

Article Classifications

Jump to section

You May Also be Interested in

Comparisons of archival and modern data suggest the Thwaites Eastern Ice Shelf thinned by 10-33% between 1978 and 2009. Image courtesy of James Yungel/NASA ICE.
Radar data on Antarctic ice sheet
Comparisons of archival and modern data suggest the Thwaites Eastern Ice Shelf thinned by 10–33% between 1978 and 2009.
Image courtesy of James Yungel/NASA ICE.
Across most ancient and modern mammalian orders, male specimens outnumber female specimens in many museum collections. Image courtesy of ddouk/pixabay.
Bias in mammalian specimen collections
Across most ancient and modern mammalian orders, male specimens outnumber female specimens in many museum collections.
Image courtesy of Pixabay/ddouk.
QnAs with NAS member and parasitologist Patricia Johnson. Image courtesy of Joy Ahn (University of California, Los Angeles, CA).
Featured QnAs
QnAs with NAS member and parasitologist Patricia Johnson
Image courtesy of Joy Ahn (University of California, Los Angeles, CA).

Similar Articles