Search

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.

Cerebral gene expression is known to be significantly influenced by a sublethal ischemic event (pre-conditioning; PC) that induces tolerance to future damaging ischemic events. Small non-coding RNAs known as microRNAs (miRNAs) were recently shown to control the mRNA translation. We currently profiled cerebral miRNAs in the cerebral cortex of rats subjected to PC. The miRNAome reacted quickly and by 6 h following PC, levels of 51 miRNAs were altered (26 up- and 25 down-regulated;1.5-fold change). Twenty of these stayed at the altered level even at 3 days after PC. At least nine miRNAs showed5-fold change at one or more time points between 6 h to 3 days after PC compared with sham. Bioinformatics analysis showed 2007 common targets of the miRNAs that were up-regulated and 459 common targets of the miRNAs that were down-regulated after PC. Pathways analysis showed that MAP-kinase and Mammalian target of rapamycin (mTOR) signaling are the top two Kyoto Encyclopedia of Genes and Genomes pathways targeted by the up-regulated miRNAs, and Wnt and GnRH signaling are the top two Kyoto Encyclopedia of Genes and Genomes pathways targeted by the down-regulated miRNAs after PC. We hypothesize that alterations in miRNAs and their down-stream mRNAs of signaling pathways might play a role in the induction of ischemic tolerance.

J. Neurochem. (2010) 113, 1685–1691. Abstract Cerebral gene expression is known to be significantly influenced by a sublethal ischemic event (pre-conditioning; PC) that induces tolerance to future damaging ischemic events. Small non-coding RNAs known as microRNAs (miRNAs) were recently shown to control the mRNA translation. We currently profiled cerebral miRNAs in the cerebral cortex of rats subjected to PC. The miRNAome reacted quickly and by 6 h following PC, levels of 51 miRNAs were altered (26 up- and 25 down-regulated; > 1.5-fold change). Twenty of these stayed at the altered level even at 3 days after PC. At least nine miRNAs showed > 5-fold change at one or more time points between 6 h to 3 days after PC compared with sham. Bioinformatics analysis showed 2007 common targets of the miRNAs that were up-regulated and 459 common targets of the miRNAs that were down-regulated after PC. Pathways analysis showed that MAP-kinase and Mammalian target of rapamycin (mTOR) signaling are the top two Kyoto Encyclopedia of Genes and Genomes pathways targeted by the up-regulated miRNAs, and Wnt and GnRH signaling are the top two Kyoto Encyclopedia of Genes and Genomes pathways targeted by the down-regulated miRNAs after PC. We hypothesize that alterations in miRNAs and their down-stream mRNAs of signaling pathways might play a role in the induction of ischemic tolerance.