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Inflammatory bowel disease
Original research
NAIL: an evolutionarily conserved lncRNA essential for licensing coordinated activation of p38 and NFκB in colitis
  1. Semih Can Akıncılar1,
  2. Lele Wu1,
  3. Qin Feng NG1,
  4. Joelle Yi Heng Chua1,
  5. Bilal Unal1,
  6. Taichi Noda2,
  7. Wei Hong Jeff Chor1,
  8. Masahito Ikawa2,
  9. Vinay Tergaonkar1,3
  1. 1 Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Institute of Molecular and Cell Biology, Singapore
  2. 2 Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
  3. 3 Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore
  1. Correspondence to Vinay Tergaonkar, Institute of Molecular and Cell Biology, 138673, Singapore; vinayt{at}imcb.a-star.edu.sg

Abstract

Objective NFκB is the key modulator in inflammatory disorders. However, the key regulators that activate, fine-tune or shut off NFκB activity in inflammatory conditions are poorly understood. In this study, we aim to investigate the roles that NFκB-specific long non-coding RNAs (lncRNAs) play in regulating inflammatory networks.

Design Using the first genetic-screen to identify NFκB-specific lncRNAs, we performed RNA-seq from the p65-/- and Ikkβ -/- mouse embryonic fibroblasts and report the identification of an evolutionary conserved lncRNA designated mNAIL (mice) or hNAIL (human). hNAIL is upregulated in human inflammatory disorders, including UC. We generated mNAILΔNFκB mice, wherein deletion of two NFκB sites in the proximal promoter of mNAIL abolishes its induction, to study its function in colitis.

Results NAIL regulates inflammation via sequestering and inactivating Wip1, a known negative regulator of proinflammatory p38 kinase and NFκB subunit p65. Wip1 inactivation leads to coordinated activation of p38 and covalent modifications of NFκB, essential for its genome-wide occupancy on specific targets. NAIL enables an orchestrated response for p38 and NFκB coactivation that leads to differentiation of precursor cells into immature myeloid cells in bone marrow, recruitment of macrophages to inflamed area and expression of inflammatory genes in colitis.

Conclusion NAIL directly regulates initiation and progression of colitis and its expression is highly correlated with NFκB activity which makes it a perfect candidate to serve as a biomarker and a therapeutic target for IBD and other inflammation-associated diseases.

  • chronic ulcerative colitis
  • inflammation
  • inflammatory bowel disease

Data availability statement

Data are available in a public, open access repository. RNA sequencing data of MEF cells (GSE157476 - https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE157476) and RNA-sequencing data of mice colon tissues (GSE138235- https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE138235) were deposited in GEO open access repository.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/gutjnl-2020-322980

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    Data availability statement

    Data are available in a public, open access repository. RNA sequencing data of MEF cells (GSE157476 - https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE157476) and RNA-sequencing data of mice colon tissues (GSE138235- https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE138235) were deposited in GEO open access repository.

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    Supplementary materials

    Footnotes

    • SCAınıl and LW contributed equally.

    • Contributors SCA, BU and VT conceived the study and designed the experiments. LW and BU performed mechanistic experiments with the help of QFN. SCA, LW performed mouse DSS modelling experiments with the help of QFN, TN and MI generated mNAIL-ΔNFκB mice. JYHC performed RNA-seq and bioinformatics analyses. VT directed the study and wrote the paper with LW and SCA.

    • Funding VT lab is supported by NRF-CRP17-2017-02 grant and core funding from IMCB A*STAR. This research is supported by the Singapore Ministry of Health’s National Medical Research Council (NMRC/OFYIRG/18MAY-0008 to SCA). BU was supported by the SINGA scholarship awarded by A*STAR, Singapore. Ikawa lab. is supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT)/Japan Society for the Promotion of Science (JSPS) KAKENHI grants (JP18K14612 to TN and JP17H01394 to MI).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.