NAIL: an evolutionarily conserved lncRNA essential for licensing coordinated activation of p38 and NFκB in colitis

NAIL: an evolutionarily conserved lncRNA essential for licensing coordinated activation of p38 and NFκB in colitis
Title:
NAIL: an evolutionarily conserved lncRNA essential for licensing coordinated activation of p38 and NFκB in colitis
Other Titles:
Gut
Keywords:
Publication Date:
25 November 2020
Citation:
Akıncılar SC, Wu L, NG QF, et al. Gut Epub ahead of print:24/11/2020. doi:10.1136/ gutjnl-2020-322980
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.
License type:
http://creativecommons.org/licenses/by-nc/4.0/
Funding Info:
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).
Description:
ISSN:
0017-5749
1468-3288
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