Genetic Models Reveal cis and trans Immune-Regulatory Activities for lincRNA-Cox2

• Published in: Cell reports (Cambridge) 2018-11, Vol.25 (6), p.1511-1524.e6
• Main Authors: Elling, Roland, Robinson, Elektra K., Shapleigh, Barbara, Liapis, Stephen C., Covarrubias, Sergio, Katzman, Sol, Groff, Abigail F., Jiang, Zhaozhao, Agarwal, Shiuli, Motwani, Mona, Chan, Jennie, Sharma, Shruti, Hennessy, Elizabeth J., FitzGerald, Garret A., McManus, Michael T., Rinn, John L., Fitzgerald, Katherine A., Carpenter, Susan
• Format: Article
• Language: English
• Subjects: Animals; CRISPR/Cas9; CRISPRi; Cyclooxygenase 2 - metabolism; Enhancer Elements, Genetic - genetics; Gene Deletion; Gene Expression Regulation; HEK293 Cells; Humans; Immunity - genetics; inflammation; innate immunity; lincRNA-Cox2; Lipopolysaccharides - pharmacology; Lung - metabolism; Macrophages - metabolism; Mice, Inbred C57BL; Mice, Knockout; Models, Genetic; Mutation - genetics; Ptgs2; RNA - metabolism; RNA Splicing - genetics; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Spleen - metabolism; Transcription, Genetic
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.10.027

An inducible gene expression program is a hallmark of the host inflammatory response. Recently, long intergenic non-coding RNAs (lincRNAs) have been shown to regulate the magnitude, duration, and resolution of these responses. Among these is lincRNA-Cox2, a dynamically regulated gene that broadly controls immune gene expression. To evaluate the in vivo functions of this lincRNA, we characterized multiple models of lincRNA-Cox2-deficient mice. LincRNA-Cox2-deficient macrophages and murine tissues had altered expression of inflammatory genes. Transcriptomic studies from various tissues revealed that deletion of the lincRNA-Cox2 locus also strongly impaired the basal and inducible expression of the neighboring gene prostaglandin-endoperoxide synthase (Ptgs2), encoding cyclooxygenase-2, a key enzyme in the prostaglandin biosynthesis pathway. By utilizing different genetic manipulations in vitro and in vivo, we found that lincRNA-Cox2 functions through an enhancer RNA mechanism to regulate Ptgs2. More importantly, lincRNA-Cox2 also functions in trans, independently of Ptgs2, to regulate critical innate immune genes in vivo. [Display omitted] •Study of lincRNA-Cox2 in vivo using recently generated KO and splicing mutant mice•lincRNA-Cox2 functions through an enhancer RNA mechanism to regulate Ptgs2 levels•lincRNA-Cox2 has a trans regulatory role controlling many innate immune genes•The lincRNA locus simultaneously regulates the expression of local and distant genes Elling et al. utilize a number of lincRNA-Cox2 genetic models to show that lincRNA-Cox2 can regulate its neighboring gene Ptgs2 (Cox2) through an enhancer RNA mechanism. They generate a lincRNA-Cox2 splicing-deficient mouse and confirm that lincRNA-Cox2 functions in trans to regulate immune genes following LPS-induced endotoxic shock.