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

Summary 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 ( Ptgs 2), 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 Ptgs 2. More importantly, lincRNA-Cox2 also functions in trans , independently of Ptgs2, to regulate critical innate immune genes in vivo .