Promoter RNA links transcriptional regulation of inflammatory pathway genes

Masayuki Matsui, Yongjun Chu, Huiying Zhang, Keith T. Gagnon, Sarfraz Shaikh, Satya Kuchimanchi, David R. Corey, Bethany A. Janowski

Research output: Contribution to journalArticle

96 Scopus citations

Abstract

Although many long non-coding RNAs (lncRNAs) have been discovered, their function and their association with RNAi factors in the nucleus have remained obscure. Here, we identify RNA transcripts that overlap the cyclooxygenase-2 (COX-2) promoter and contain two adjacent binding sites for an endogenous miRNA, miR-589. We find that miR-589 binds the promoter RNA and activates COX-2 transcription. In addition to miR-589, fully complementary duplex RNAs that target the COX-2 promoter transcript activate COX-2 transcription. Activation by small RNA requires RNAi factors argonaute-2 (AGO2) and GW182, but does not require AGO2-mediated cleavage of the promoter RNA. Instead, the promoter RNA functions as a scaffold. Binding of AGO2 protein/small RNA complexes to the promoter RNA triggers gene activation. Gene looping allows interactions between the promoters of COX-2 and phospholipase A2 (PLA2G4A), an adjacent pro-inflammatory pathway gene that produces arachidonic acid, the substrate for COX-2 protein. miR-589 and fully complementary small RNAs regulate both COX-2 and PLA2G4A gene expression, revealing an unexpected connection between key steps of the eicosanoid signaling pathway. The work demonstrates the potential for RNA to coordinate locus-dependent assembly of related genes to form functional operons through cis-looping.

Original languageEnglish (US)
Pages (from-to)10086-10109
Number of pages24
JournalNucleic acids research
Volume41
Issue number22
DOIs
StatePublished - Dec 1 2013

ASJC Scopus subject areas

  • Genetics

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    Matsui, M., Chu, Y., Zhang, H., Gagnon, K. T., Shaikh, S., Kuchimanchi, S., Corey, D. R., & Janowski, B. A. (2013). Promoter RNA links transcriptional regulation of inflammatory pathway genes. Nucleic acids research, 41(22), 10086-10109. https://doi.org/10.1093/nar/gkt777