| First Author | Akıncılar SC | Year | 2020 |
| Journal | Gut | PubMed ID | 33239342 |
| Mgi Jnum | J:303079 | Mgi Id | MGI:6511547 |
| Doi | 10.1136/gutjnl-2020-322980 | Citation | Akincilar SC, et al. (2020) NAIL: an evolutionarily conserved lncRNA essential for licensing coordinated activation of p38 and NFkappaB in colitis. Gut |
| abstractText | OBJECTIVE: NFkappaB is the key modulator in inflammatory disorders. However, the key regulators that activate, fine-tune or shut off NFkappaB activity in inflammatory conditions are poorly understood. In this study, we aim to investigate the roles that NFkappaB-specific long non-coding RNAs (lncRNAs) play in regulating inflammatory networks. DESIGN: Using the first genetic-screen to identify NFkappaB-specific lncRNAs, we performed RNA-seq from the p65(-/-) and Ikkbeta (-/-) 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 mNAIL(DeltaNFkappaB) mice, wherein deletion of two NFkappaB 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 NFkappaB subunit p65. Wip1 inactivation leads to coordinated activation of p38 and covalent modifications of NFkappaB, essential for its genome-wide occupancy on specific targets. NAIL enables an orchestrated response for p38 and NFkappaB 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 NFkappaB activity which makes it a perfect candidate to serve as a biomarker and a therapeutic target for IBD and other inflammation-associated diseases. |
