title: Mutual induction of transcription factor PPARγ and microRNAs miR-145 and miR-329.
abstract: MicroRNAs (miRNAs) are small non-coding RNAs that are known to control mRNA translation. Most miRNAs are transcribed from specific genes with well-defined promoters located throughout the genome. The mechanisms that control miRNA expression under normal and pathological conditions are not yet understood clearly. Peroxisome proliferator-activated receptor (PPAR) γ is a ligand-activated transcription factor that is extensively distributed in the CNS. PPARγ activation induces neuroprotection by modulating genes that contain peroxisome proliferator response elements (PPREs) in their promoters. We presently evaluated if PPARγ modulates miRNA expression. When adult rats were treated with PPARγ agonist rosiglitazone, expression of 28 miRNAs altered significantly (12 up- and 16 down-regulated; 3-119 fold) in the cerebral cortex compared to vehicle-treated controls. In silico analysis showed 1-5 PPREs in the putative promoter regions (within 1 Kb upstream of the transcription start site) of these miRNA genes. Cotransfection with a PPARγ constitutively expressing vector significantly induced the miR-145 and miR-329 promoter vectors (each have four PPREs), which was curtailed by point mutations of PPREs in their promoters. Interestingly, the PPARγ promoter has binding sites for both these miRNAs and transfection with miR-329 mimic and miR-145 mimic induced the PPARγ expression. Thus, these studies show a cyclical induction of miRNAs and PPARγ, indicating that the pleiotropic beneficial effects of PPARγ agonists might be modulated in part by miRNAs and their down-stream mRNAs. We proposed that promoters of many microRNAs contain the binding sites for the transcription factor PPARγ. Activation of PPARγ modulates the expression of these microRNAs. Two such PPARγ-responsive microRNAs (miR-145 and miR-329) bind to PPARγ promoter to induce its expression. This indicates the presence of a feedback loop by which transcription factors and microRNAs can modulate each other.
authors.affiliation: Department of Neurological Surgery and Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Dharap
authors.affiliation: Department of Neurological Surgery and Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Pokrzywa
authors.affiliation: Department of Neurological Surgery and Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Shruthi
authors.initials: S
authors.lastname: Murali
authors.affiliation: Department of Neurological Surgery and Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Balarama
authors.initials: B
authors.lastname: Kaimal
authors.affiliation: Department of Neurological Surgery and Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Raghu
authors.initials: R
authors.lastname: Vemuganti
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D047495:PPAR gamma / Q000235:genetics*; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection / Q000379:methods
chemical_list: C542511:MIRN145 microRNA, rat; D035683:MicroRNAs; D047495:PPAR gamma; D045162:Thiazolidinediones; D014157:Transcription Factors; C000604040:miR-329, rat; D000077154:Rosiglitazone
keywords: gene induction; miRNA; non-coding RNA; peroxisome proliferator-activated receptor; promoters; transcription factor