p50-associated COX-2 extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-κB complexes.
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, a 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.DOI: http://dx.doi.org/10.7554/eLife.01776.001.
Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States.
Michal
M
Krawczyk
Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States emerson@salk.edu.
Beverly M
BM
Emerson
D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004847:Epithelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D009000:Monocytes / Q000502:physiology*; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors*; D022661:RNA, Untranslated / Q000378:metabolism*; D014158:Transcription, Genetic
D052002:NF-kappa B p50 Subunit; D022661:RNA, Untranslated; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
CTCF; Cyclooxygenase 2; NF-κB; long non-coding RNA; p300; transcription