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Cell Rep. 2018 Nov 6;25(6):1511-1524.e6. doi: 10.1016/j.celrep.2018.10.027.

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

Author information

1
Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA; Center for Pediatrics, Department of General Pediatrics, University of Freiburg, Freiburg, Germany.
2
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA, USA.
3
Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA.
4
Center for Biomolecular Science and Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
5
Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
6
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Smilow, Philadelphia, PA 19104, USA.
7
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
8
Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA; Department of Biochemistry, BioFrontiers, University of Colorado Boulder, Boulder, CO 80301, USA.
9
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA, USA. Electronic address: sucarpen@ucsc.edu.

Abstract

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

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