title: Increased precursor microRNA-21 following status epilepticus can compete with mature microRNA-21 to alter translation.
abstract: MicroRNA-21 (miR-21) is consistently up-regulated in various neurological disorders, including epilepsy. Here, we show that the biogenesis of miR-21 is altered following pilocarpine-induced status epilepticus (SE) with an increase in precursor miR-21 (pre-miR-21) in rats. We demonstrate that pre-miR-21 has an energetically favorable site overlapping with the miR-21 binding site and competes with mature miR-21 for binding in the 3'UTR of TGFBR2 mRNA, but not NT-3 mRNA in vitro. This binding competition influences miR-21-mediated repression in vitro and correlates with the increase in TGFBR2 and decrease in NT-3 following SE. Polysome profiling reveals co-localization of pre-miR-21 in the ribosome fraction with translating mRNAs in U-87 cells. The current work suggests that pre-miR-21 may post-transcriptionally counteract miR-21-mediated suppression following SE and could potentially lead to prolonged TGF-β receptor expression impacting epileptogenesis. The study further supports that the ratio of the pre to mature miRNA may be important in determining the regulatory effects of a miRNA gene.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA USA.
authors.forename: Kayam
authors.initials: K
authors.lastname: Chak
authors.affiliation: Departments of Pediatrics and Genetics, Stanford University, Stanford, CA USA.
authors.forename: Biswajoy
authors.initials: B
authors.lastname: Roy-Chaudhuri
authors.affiliation: Departments of Pediatrics and Genetics, Stanford University, Stanford, CA USA.
authors.forename: Hak Kyun
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Departments of Pediatrics and Genetics, Stanford University, Stanford, CA USA.
authors.forename: Kayla C
authors.initials: KC
authors.lastname: Kemp
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA USA. Electronic address: brenda2@stanford.edu.
authors.forename: Brenda E
authors.initials: BE
authors.lastname: Porter
authors.affiliation: Departments of Pediatrics and Genetics, Stanford University, Stanford, CA USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Kay
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019295:Computational Biology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018721:Muscarinic Agonists / Q000633:toxicity; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D020933:Neurotrophin 3; D010862:Pilocarpine / Q000633:toxicity; D014176:Protein Biosynthesis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D013226:Status Epilepticus / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D018721:Muscarinic Agonists; C000595808:NTF3 protein, human; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D010862:Pilocarpine; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: Pilocarpine; Pre-miR-21; Regulation of mRNA; Status epilepticus; TGFβ receptor 2