Mutual induction of transcription factor PPARγ and microRNAs miR-145 and miR-329.
Mutual induction of transcription factor PPARγ and microRNAs miR-145 and miR-329.
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DOI：
10.1111/jnc.13220
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发表时间：
2015-10
影响因子：
4.7
通讯作者：
Vemuganti R
中科院分区：
文献类型：
--
作者：
Dharap A;Pokrzywa C;Murali S;Kaimal B;Vemuganti R
微小RNA（miRNAs）是一类小型非编码RNA，已知其可调控信使RNA（mRNA）的翻译。大多数miRNAs是由基因组中具有明确启动子的特定基因转录而来。在正常和病理条件下调控miRNA表达的机制尚未完全清楚。过氧化物酶体增殖物激活受体（PPAR）γ是一种配体激活的转录因子，广泛分布于中枢神经系统（CNS）。PPARγ的激活通过调节其启动子中含有过氧化物酶体增殖物反应元件（PPREs）的基因来诱导神经保护作用。我们目前评估了PPARγ是否调节miRNA的表达。当成年大鼠接受PPARγ激动剂罗格列酮治疗时，与溶媒处理的对照组相比，大脑皮质中28种miRNAs的表达发生了显著改变（12种上调，16种下调；3到119倍）。计算机模拟分析显示，在这些miRNA基因的假定启动子区域（转录起始位点上游1kb以内）存在1到5个PPREs。与持续表达PPARγ的载体共转染显著诱导了miR - 145和miR - 329启动子载体（每个都有4个PPREs），而其启动子中PPREs的点突变则抑制了这种诱导作用。有趣的是，PPARγ启动子具有这两种miRNAs的结合位点，并且用miR - 329模拟物和miR - 145模拟物转染可诱导PPARγ的表达。因此，这些研究表明miRNAs和PPARγ之间存在循环诱导，这意味着PPARγ激动剂的多效性有益作用可能部分受到miRNAs及其下游mRNAs的调节。
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 to 119 fold) in the cerebral cortex compared to vehicle-treated controls. In silico analysis showed 1 to 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 4 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.