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首页> 外文期刊>Biochimica et Biophysica Acta. Gene Regulatory Mechanisms >Regulation of the neuronal transcription factor NPAS4 by REST and microRNAs
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Regulation of the neuronal transcription factor NPAS4 by REST and microRNAs

机译:REST和microRNA对神经元转录因子NPAS4的调节

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NPAS4 is a brain restricted, activity-induced transcription factor which regulates the expression of inhibitory synapse genes to control homeostatic excitatory/inhibitory balance in neurons. NPAS4 is required for normal social interaction and contextual memory formation in mice. Protein and mRNA expression of NPAS4 is tightly coupled to neuronal depolarization and most prevalent in the cortical and hippocampal regions in the brain, however the precise mechanisms by which the NPAS4 gene is controlled remain unexplored. Here we show that expression of NPAS4 mRNA is actively repressed by RE-1 silencing transcription factoreuron-restrictive silencer factor (REST/NRSF) in embryonic stem cells and non-neuronal cells by binding multiple sites within the promoter and Intron I of NPAS4. Repression by REST also appears to correlate with the binding of the zinc finger DNA binding protein CTCF within Intron I of NPAS4. In addition, we show that the 3' untranslated region (3'UTR) of NPAS4 can be targeted by two microRNAs, miR-203 and miR-224 to further regulate its expression. miR-224 is a midbrain/hypothalamus enriched microRNA which is expressed from an intron within the GABAA receptor epsilon (GABRE) gene and may further regionalize NPAS4 expression. Our results reveal REST and microRNA dependent mechanisms that restrict NPAS4 expression to the brain.
机译:NPAS4是一种受大脑限制的,由活性诱导的转录因子,可调节抑制性突触基因的表达,以控制神经元中的稳态兴奋/抑制平衡。 NPAS4是小鼠正常社交互动和情境记忆形成所必需的。 NPAS4的蛋白质和mRNA表达与神经元去极化紧密相关,并且在大脑的皮质和海马区最为普遍,然而,仍未探索控制NPAS4基因的确切机制。在这里,我们表明,NP-1 4的启动子和内含子I结合在胚胎干细胞和非神经元细胞中,RE-1沉默转录因子/中子限制性沉默因子(REST / NRSF)积极抑制了NPAS4 mRNA的表达。 。 REST抑制也似乎与NPAS4内含子I中锌指DNA结合蛋白CTCF的结合有关。此外,我们显示NPAS4的3'非翻译区(3'UTR)可以被miR-203和miR-224这两个microRNA靶向,以进一步调节其表达。 miR-224是富含中脑/下丘脑的microRNA,从GABAA受体epsilon(GABRE)基因内含子表达,并且可能进一步使NPAS4表达区域化。我们的研究结果揭示了REST和microRNA依赖性机制将NPAS4表达限制在大脑中。

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