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

Michal Krawczyk, Beverly Emerson

Research output: Contribution to journalArticle

127 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Long Noncoding RNA
Gene expression
RNA
Gene Expression
Chromatin
Histone Acetyltransferases
Acetylation
RNA Polymerase II
Macrophages
Genetic Promoter Regions
Dimers
Histones
Monocytes
Neoplasms
Breast
Genes
Epithelial Cells
Chemical activation
Cells
Modulation

Keywords

  • Anti-sense transcripts
  • Cancer
  • CTCF
  • 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)
  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

P50-associated COX-2 Extragenic RNA (pacer) activates human COX-2 gene expression by occluding repressive NF-κB p50 complexes. / Krawczyk, Michal; Emerson, Beverly.

In: eLife, Vol. 2014, No. 3, e01776, 29.04.2014.

Research output: Contribution to journalArticle

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