Regulation and function of the ERV-lncRNAs in postmitotic neurons

刺激诱导神经元成熟和可塑性的确切机制已经在分子、细胞和神经网络水平上进行了研究，可能涉及基因表达、蛋白质合成和细胞/解剖结构变化的组合。近年来，人们对基因调控机制进行了广泛的研究，这些机制可以在短时间内促进初始获取，同时在较长时间内持续进行，以允许长期整合。这引起了人们对染色质调控过程的极大兴趣，而染色质调控并不是DNA本身固有的。令人兴奋的新研究表明，包括长链非编码rna （lncRNAs）在内的调控元件负责介导这些变化。内源性逆转录病毒（ERV）通过产生lncRNAs介导的基因调控和染色质重塑（ERV-lncRNAs）是一个新兴课题。我们的中心假设是，在有丝分裂后神经元成熟过程中经历的外部刺激会产生特异性lncRNA谱的强烈变化，因此，对erv -lncRNA表达和调控网络的综合分析有望为协调正常脑细胞反应和神经系统疾病的基因表达机制提供根本性的新见解。我们试图在以下三个相互关联的特定目标中验证这一工作假设：1)研究有丝分裂后神经元在存在和缺乏外部刺激的情况下erv - lncrna的调控。我们的目标是进行最先进的基因组和表观基因组测序，以探索有丝分裂后神经元中lncRNAs调控网络和基因表达模式之间潜在的新联系。2)确定目标ERV-lncRNA的功能相关性。我们的目标是使用我们开发/进展的方法，通过功能丧失和功能获得的研究来操纵有丝分裂后神经元中特定的ERV-lncRNA表达，以确定其在改变基因表达中的因果作用。3) ATRX对神经元ERV-lncRNAs表达影响的研究。我们建议通过检查ATRX对ERV-lncRNAs表达的影响，将我们对受刺激神经元中ERV-lncRNAs的研究扩展到疾病范式。ATRX是染色质重塑因子的一员，其功能丧失突变导致复杂的神经综合征。总的来说，我们的研究将为神经元激活的表观基因组调控提供新的和关键的信息。鉴定染色质状态改变的基因和基因网络将有助于更好地描述神经元激活关键时期的表观遗传景观。这些新知识有可能导致旨在减少神经系统疾病进展的新疗法的发展。

The precise mechanisms underlying stimulation induced neuronal maturation and plasticity have been subject to studies at the molecular, cellular and neuronal network levels and are likely to involve a combination of changes in gene expression, protein synthesis and cellular/anatomical structure. In recent years, there has been an extensive search for gene regulatory mechanisms that respond within short timescales to promote initial acquisition, while persisting over longer timescales to allow for long-term consolidation. This has prompted much interest in the process of chromatin regulation that is not hardwired in DNA itself. Exciting new research suggests that regulatory elements including long noncoding RNAs (lncRNAs) are responsible for mediating such changes. Endogenous retrovirus (ERV) mediated gene regulation and chromatin remodeling via the production of lncRNAs (ERV-lncRNAs) is an emerging topic. Our central hypothesis is that external stimuli experienced during postmitotic neuronal maturation generate robust changes in specific lncRNA profiles, such that comprehensive analyses of ERV-lncRNAs expression and regulatory network promise to provide fundamentally novel insights into the gene expression mechanism orchestrating normal brain cell response and neurological disease. We seek to test this working hypothesis in the following three interrelated Specific Aims: 1) Studies of ERVs-lncRNAs regulation in postmitotic neurons in the presence and absence of external stimulation. We aim to perform state-of-the-art genome and epigenome sequencing to explore potential novel links between the lncRNAs regulatory network and patterns of gene expression in the context of postmitotic neurons followed by external stimulation. 2) Determine the functional relevance of a target ERV-lncRNA. We aim to use our developed/progressing methods to manipulate a specific ERV-lncRNA expression in postmitotic neurons, via both loss-of-function and gain-of-function studies, to determine its causal role in altering gene expression. 3) Studies of the impact of ATRX on ERV-lncRNAs expression in neurons. We propose to extend our work on ERV-lncRNAs in stimulated neurons to the disease paradigm by examining the impact of ATRX, a member of chromatin remodeling factors whose loss-of-function mutations cause a complex neurological syndrome, on ERV-lncRNAs expression. Collectively our studies will provide novel and critical information regarding the epigenome regulation across neuronal activation. Identification of genes and gene networks with altered chromatin status will help to better describe the epigenetic landscape during critical period of neuronal activation. Such new knowledge has the potential to lead to the development of novel treatments aimed at reducing the progression of neurological illnesses.