Epigenetic regulation of microRNAs in neurogenesis

描述(由申请人提供)：神经发生中组蛋白脱乙酰酶(HDAC)抑制剂如丙戊酸(VPA)通常用于治疗癫痫。其疗效的一种机制可能是表观遗传对神经前体分化的影响。虽然HDAC抑制剂可能会影响mRNA编码基因，但我们认为VPA处理对microRNAs的快速调节暗示了一种新的互补机制。假设：乙酰化组蛋白允许表达促进或支持神经前体神经发生的microRNA。因此，添加HDAC抑制剂允许在染色质上的microRNA编码位置积累乙酰标记，进而增强标记的microRNAs的表达，这有助于神经分化。我们将使用“深度测序”来确定VPA调节的microRNAs的全部组成，包括我们最近在神经分化中发现的数百个新的microRNAs，以检验这一假说。最后，我们将在我们使用microRNA抑制剂和筛选技术的初步研究的基础上，评估候选microRNAs对VPA诱导的神经元分化的需求。这三个目标的结果将识别已知的和可能是新的在HDAC抑制后被调控的microRNAs，位于microRNA启动子区域附近的组蛋白的乙酰化状态，以及被调控的microRNAs是否有助于神经元分化。了解神经发生所需的调控网络对于确定神经前体的分化在痴呆症、帕金森氏症或中风等情况下如何受损非常重要。或者，在癫痫、双相情感障碍或偏头痛等疾病中使用HDAC抑制剂可能会对成年前体细胞的神经发生产生意想不到的影响，这一潜在好处应该得到理解。公共卫生相关性：神经发生中microRNAs的表观遗传调控。已知的癫痫药物，如丙戊酸盐(VPA)，可以抑制组蛋白脱乙酰酶，后者从表观遗传上控制基因的表达。由于VPA还会增加成年干细胞或其他前体细胞产生的神经元，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microRNAs和基因调节区的“深度测序”来识别新的神经发生机制。

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.