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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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 R, Jiang Z, Agarwal S, Motwani M, Chan J, Sharma S, Fitzgerald KA, Carpenter S. (2018). Genetic Models Reveal cis and trans Immune-Regulatory Activities for lincRNA-Cox2. Open Access Articles. https://doi.org/10.1016/j.celrep.2018.10.027. Retrieved from https://escholarship.umassmed.edu/oapubs/3664
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