p50-Associated COX2 Extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-κB complexes

Open accessCopyright infoDownload PDFRelated content

ACCEPTED MANUSCRIPT

p50-Associated COX2 Extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-κB complexes

Affiliation details

DOI: http://dx.doi.org/10.7554/eLife.01776Published April 29, 2014 Cite as eLife 2014;10.7554/eLife.01776 Download PDF

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.

Comments

Comments are checked by a moderator (and/or an eLife editor) before they appear. Comments should be constructive, relevant to the article, conform to our terms and conditions, and include any pertinent competing interests.