Program in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology; Graduate School of Biomedical Sciences
Genetic Phenomena | Genetics and Genomics | Immunity | Nucleic Acids, Nucleotides, and Nucleosides
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.
CRISPR/Cas9, CRISPRi, Ptgs2, inflammation, innate immunity, lincRNA-Cox2
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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI of Published Version
Cell Rep. 2018 Nov 6;25(6):1511-1524.e6. doi: 10.1016/j.celrep.2018.10.027. Link to article on publisher's site
Elling, Roland; Jiang, Zhaozhao; Agarwal, Shiuli; Motwani, Mona; Chan, Jennie; Sharma, Shrutie; Fitzgerald, Katherine A.; and Carpenter, Susan, "Genetic Models Reveal cis and trans Immune-Regulatory Activities for lincRNA-Cox2" (2018). Open Access Articles. 3664.
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