title: Promoter RNA links transcriptional regulation of inflammatory pathway genes.
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.
authors.affiliation: Department of Pharmacology and Biochemistry, UT Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390-9041, USA and Alnylam Pharmaceuticals, Cambridge, MA 02142, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsui
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Chu
authors.forename: Huiying
authors.initials: H
authors.lastname: Zhang
authors.forename: Keith T
authors.initials: KT
authors.lastname: Gagnon
authors.forename: Sarfraz
authors.initials: S
authors.lastname: Shaikh
authors.forename: Satya
authors.initials: S
authors.lastname: Kuchimanchi
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: David R
authors.initials: DR
authors.lastname: Corey
authors.forename: Bethany A
authors.initials: BA
authors.lastname: Janowski
mesh_terms: D060565:Argonaute Proteins / Q000378:metabolism; D001324:Autoantigens / Q000378:metabolism; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics*; D054513:Group IV Phospholipases A2 / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012313:RNA / Q000096:biosynthesis; D016372:RNA, Antisense / Q000096:biosynthesis; D058727:RNA, Small Untranslated / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D001324:Autoantigens; D006657:Histones; C586366:MIRN589 microRNA, human; D035683:MicroRNAs; D016372:RNA, Antisense; D058727:RNA, Small Untranslated; D016601:RNA-Binding Proteins; C465663:TNRC6A protein, human; D012313:RNA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D054513:Group IV Phospholipases A2; C516389:PLA2G4A protein, human