Epigenetic regulation of microRNAs in neurogenesis

描述（由申请人提供）：神经发生组蛋白去乙酰化酶（HDAC）抑制剂（如丙戊酸酯（VPA））中microrna的表观遗传调控通常用于治疗癫痫。其作用机制可能与表观遗传对神经前体细胞分化的影响有关。虽然HDAC抑制剂可能会影响mrna编码基因，但我们认为VPA治疗对microrna的快速调节表明了一种新的互补机制。假设：乙酰化组蛋白允许microrna的表达，增强或支持神经前体的神经发生。因此，添加HDAC抑制剂可以在染色质上的microrna编码位点上积累乙酰基标记，从而增强标记microrna的表达，从而促进神经分化。我们将通过“深度测序”来验证这一假设，以鉴定vpa调节的microrna的全部补体，包括我们最近在神经分化中发现的数百种新型microrna。最后，我们将利用microRNA抑制剂和筛选技术进行初步研究，以评估候选microRNA对vpa诱导的神经元分化的需求。这三个目标的结果将确定已知的和推测的新microRNA，这些microRNA在HDAC抑制后被调节，位于microRNA启动子区域附近的组蛋白的乙酰化状态，以及被调节的microRNA是否有助于神经元分化。了解神经发生所需的调节网络对于确定神经前体的分化如何在痴呆、帕金森病或中风等疾病中受损非常重要。另外，在癫痫、双相情感障碍或偏头痛等疾病中使用HDAC抑制剂可能会对成人前体的神经发生产生意想不到的影响，并且应该了解这种潜在的益处。公共卫生相关性：神经发生中microrna的表观遗传调控。癫痫药物如丙戊酸酯（VPA）可以抑制组蛋白去乙酰化酶，而组蛋白去乙酰化酶在表观遗传上控制基因表达。由于VPA也增加了成体干细胞或其他前体神经元的产生，我们认为VPA可能调节microRNA基因，进而影响控制细胞分化的决定。我们将使用microrna和基因调控区域的“深度测序”来确定新的神经发生机制。

DESCRIPTION (provided by applicant): Epigenetic regulation of microRNAs in neurogenesis Histone deacetylase (HDAC) inhibitors such as valproate (VPA) are commonly used to treat epilepsy. One me- chanism of their efficacy may result from epigenetic effects on differentiation of neural precursors. While HDAC inhibitors are likely to affect mRNA-encoding genes, we believe that the rapid regulation of microRNAs by VPA treatment suggests a novel complementary mechanism. Hypothesis: Acetylated histones allow expression of microRNAs that enhance or support neurogenesis from neural precursors. Therefore, adding an HDAC inhibitor allows the accumulation of acetyl marks on microRNA-encoding sites on the chromatin, in turn enhancing expression of the marked microRNAs, which contribute to neural differentiation. We will test the hypothesis by using "deep sequencing" to identify the full complement of VPA-regulated microRNAs, including hundreds of novel microRNAs that we recently identified in neural differentiation. Finally, we will build on our preliminary studies with microRNA inhibitors and screening techniques to evaluate candidate microRNAs for their requirement for VPA-induced neuronal differentiation. Results from these three aims will identify both known and putatively novel microRNAs that are regulated after HDAC inhibition, the acetylation status of histones located near microRNA promoter regions, and whether the regulated microRNAs contribute to neuronal differentiation. Understanding the regulatory networks required for neurogenesis is important for determining how differentiation of neural precursors could be impaired in conditions such as dementia, Parkinson's, or stroke. Alternatively, the use of HDAC inhibitors in conditions such as epilepsy, bipolar disorder, or migraines may have unexpected effects on neurogenesis from adult precursors, and this potential benefit should be understood. PUBLIC HEALTH RELEVANCE: Epigenetic regulation of microRNAs in neurogenesis. Epilepsy drugs such as valproate (VPA) are known to inhibit histone deacetylases, which control gene expression epigenetically. Since VPA also increases the production of neurons from adult stem cells or other precursors, we believe that VPA may regulate microRNA genes, in turn affecting decisions controlling cell differentiation. We will use "deep sequencing" of microRNAs and gene regulatory regions to identify novel neurogenesis mechanisms.