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

Cell Rep. 2018 Nov 6;25(6):1511-1524.e6. 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.

Keywords: CRISPR/Cas9; CRISPRi; Ptgs2; inflammation; innate immunity; lincRNA-Cox2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclooxygenase 2 / metabolism*
  • Enhancer Elements, Genetic / genetics
  • Gene Deletion
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Immunity / genetics*
  • Lipopolysaccharides / pharmacology
  • Lung / metabolism
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Genetic*
  • Mutation / genetics
  • RNA / metabolism
  • RNA Splicing / genetics
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Spleen / metabolism
  • Transcription, Genetic


  • Lipopolysaccharides
  • RNA, Long Noncoding
  • RNA, Messenger
  • RNA
  • Cyclooxygenase 2