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

85 Citations (Scopus)

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 2013

Fingerprint

Cyclooxygenase 2
RNA
Genes
Complementary RNA
RNA Interference
Argonaute Proteins
Long Noncoding RNA
RNA Cleavage
Eicosanoids
Phospholipases A2
Operon
Prostaglandin-Endoperoxide Synthases
MicroRNAs
Transcriptional Activation
Binding Sites
Gene Expression
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Matsui, M., Chu, Y., Zhang, H., Gagnon, K. T., Shaikh, S., Kuchimanchi, S., ... 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

Promoter RNA links transcriptional regulation of inflammatory pathway genes. / Matsui, Masayuki; Chu, Yongjun; Zhang, Huiying; Gagnon, Keith T.; Shaikh, Sarfraz; Kuchimanchi, Satya; Corey, David R.; Janowski, Bethany A.

In: Nucleic Acids Research, Vol. 41, No. 22, 12.2013, p. 10086-10109.

Research output: Contribution to journalArticle

Matsui, M, Chu, Y, Zhang, H, Gagnon, KT, Shaikh, S, Kuchimanchi, S, Corey, DR & Janowski, BA 2013, 'Promoter RNA links transcriptional regulation of inflammatory pathway genes', Nucleic Acids Research, vol. 41, no. 22, pp. 10086-10109. https://doi.org/10.1093/nar/gkt777
Matsui M, Chu Y, Zhang H, Gagnon KT, Shaikh S, Kuchimanchi S et al. Promoter RNA links transcriptional regulation of inflammatory pathway genes. Nucleic Acids Research. 2013 Dec;41(22):10086-10109. https://doi.org/10.1093/nar/gkt777
Matsui, Masayuki ; Chu, Yongjun ; Zhang, Huiying ; Gagnon, Keith T. ; Shaikh, Sarfraz ; Kuchimanchi, Satya ; Corey, David R. ; Janowski, Bethany A. / Promoter RNA links transcriptional regulation of inflammatory pathway genes. In: Nucleic Acids Research. 2013 ; Vol. 41, No. 22. pp. 10086-10109.
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