Epigenetic regulation of microRNAs in neurogenesis

microRNA在神经发生中的表观遗传调控

基本信息

批准号：
7738740
负责人：
RONALD P HART
金额：
$ 23.05万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7738740
关键词：
Acetylation Adverse effects Affect Antibodies Bipolar Disorder Cell Differentiation process Cells Chromatin Complement Complex Development Epigenetic Process Epilepsy Evaluation Gene Expression Genes Genome Glial Fibrillary Acidic Protein Histone Deacetylase Histone Deacetylase Inhibitor Histone deacetylase inhibition Histones Individual Measures Mediating Messenger RNA MicroRNAs Migraine Neuronal Differentiation Neurons Nucleic Acid Regulatory Sequences Parkinson&apos s Dementia Pharmaceutical Preparations Production Promoter Regions RNA Regulation Screening procedure Site Small RNA Stroke Techniques Technology Testing adult neurogenesis adult stem cell design inhibitor/antagonist nerve stem cell nestin protein neural precursor cell neurogenesis novel promoter protein expression public health relevance relating to nervous system research study valproate

项目摘要

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.

描述（由申请人提供）：神经发生组蛋白脱乙酰基酶（HDAC）抑制剂（如丙戊酸）（VPA）的表观遗传调节通常用于治疗癫痫。它们的功效的一种我可能是由于对神经前体的分化的表观遗传作用而引起的。尽管HDAC抑制剂可能会影响mRNA编码基因，但我们认为通过VPA处理对microRNA的快速调节表明了一种新型的互补机制。假设：乙酰化组蛋白允许表达microRNA，从而增强或支持神经前体神经发生。因此，添加HDAC抑制剂允许在染色质上的microRNA编码位点上积聚乙酰标记，从而增强了标记的microRNA的表达，从而有助于神经分化。我们将通过使用“深层测序”来检验假设，以确定VPA调节的microRNA的完整补体，包括我们最近在神经分化中发现的数百种新型microRNA。最后，我们将以microRNA抑制剂和筛查技术的初步研究为基础，以评估候选microRNAS对VPA诱导的神经元分化的需求。这三个目标的结果将确定HDAC抑制后受调节的已知和新颖的microRNA，位于microRNA启动子区域附近的组蛋白的乙酰化状态以及调节的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在痴呆症，帕金森氏症或中风等条件下如何损害神经前体的分化很重要。或者，在癫痫，躁郁症或偏头痛等条件下使用HDAC抑制剂可能会对成人前体的神经发生产生意外影响，因此应了解这种潜在的益处。公共卫生相关性：神经发生中microRNA的表观遗传调节。已知癫痫药物（例如丙戊酸）（VPA）抑制组蛋白脱乙酰基酶，这些乙酰基酶表观遗传控制基因表达。由于VPA还增加了成人干细胞或其他前体的神经元的产生，因此我们认为VPA可能调节microRNA基因，进而影响控制细胞分化的决策。我们将使用microRNA和基因调节区域的“深度测序”来鉴定新的神经发生机制。