1. Chromosomes and Gene Expression
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p50-Associated COX2 Extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-κB complexes

  1. Michal Krawczyk
  2. Beverly M Emerson  Is a corresponding author
  1. Salk Institute for Biological Studies, United States
Research Article
  • Cited 156
  • Views 2,431
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Cite this article as: eLife 2014;3:e01776 doi: 10.7554/eLife.01776

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.

Article and author information

Author details

  1. Michal Krawczyk

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Beverly M Emerson

    Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    emerson@salk.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Joaquin M Espinosa, HHMI / University of Colorado at Boulder, United States

Publication history

  1. Received: October 24, 2013
  2. Accepted: April 11, 2014
  3. Accepted Manuscript published: April 29, 2014 (version 1)
  4. Version of Record published: May 13, 2014 (version 2)

Copyright

© 2014, Krawczyk et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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