Mutual induction of transcription factor PPARγ and microRNAs miR-145 and miR-329

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) gamma is a ligand-activated transcription factor that is extensively distributed in the CNS. PPAR gamma activation induces neuroprotection by modulating genes that contain peroxisome proliferator response elements (PPREs) in their promoters. We presently evaluated if PPAR gamma modulates miRNA expression. When adult rats were treated with PPAR gamma 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 PPAR gamma 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 PPAR gamma promoter has binding sites for both these miRNAs and transfection with miR-329 mimic and miR-145 mimic induced the PPAR gamma expression. Thus, these studies show a cyclical induction of miRNAs and PPAR gamma, indicating that the pleiotropic beneficial effects of PPARc agonists might be modulated in part by miRNAs and their down-stream mRNAs.