P50-associated COX-2 Extragenic RNA (pacer) activates human COX-2 gene expression by occluding repressive NF-κB p50 complexes

Michal Krawczyk, Beverly M. Emerson

Research output: Contribution to journalArticle

137 Scopus citations

Abstract

Deregulated expression of COX-2 has been causally linked to development, progression and outcome of several types of human cancer. We describe a novel fundamental level of transcriptional control of COX-2 expression. Using primary human mammary epithelial cells and monocyte/macrophage cell lines we show that the chromatin boundary/insulator factor CTCF establishes an open chromatin domain and induces expression of a long non-coding RNA within the upstream promoter region of COX-2. Upon induction of COX-2 expression, the lncRNA associates with p50, a repressive subunit of NF-κB, and occludes it from the COX-2 promoter, potentially facilitating interaction with activation-competent NF-κB p65/p50 dimers. This enables recruitment of the p300 histone acetyltransferase, domain-wide increase in histone acetylation and assembly of RNA Polymerase II initiation complexes. Our findings reveal an unexpected mechanism of gene control by lncRNA-mediated repressor occlusion and identify the COX-2-lncRNA, PACER, as a new potential target for COX-2-modulation in inflammation and cancer.

Original languageEnglish (US)
Article numbere01776
JournaleLife
Volume2014
Issue number3
DOIs
StatePublished - Apr 29 2014

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Keywords

  • Anti-sense transcripts
  • CTCF
  • Cancer
  • Cyclooxygenase 2
  • Divergent promoters
  • Histone acetylation
  • Long non-coding RNA
  • Monocyte-macrophage differentiation
  • NF-κB
  • P300
  • RNA polymerase II recruitment
  • Transcription

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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