The epigenetic mechanism of enhancer RNA in behavioral plasticity

描述（由申请人提供）： 大量证据表明，许多神经系统疾病通常可能是由神经功能中活动依赖性变化的扰动引起的。在大脑发育期间，个体神经元和回路的感觉刺激依赖性调节不仅涉及局部突触连接的结构和功能变化，还涉及持续适应性反应的细胞范围内的排列。感觉经验依赖性基因表达是全细胞适应的一个组成机制，因为它负责刺激特异性生产和部署具有各种功能的蛋白质在单个神经元中，这是适当的适应性反应所必需的。与这一概念相一致的是，涉及从突触到细胞核的信号通路的几个基因的突变与各种神经系统疾病（如自闭症和癫痫）有关，这表明在特定情况下，活动依赖性基因表达程序的破坏，如活动依赖性学习，可能会引起病理生理学状况。因此，了解遗传和表观遗传程序如何准确地将感觉信息转化为相关神经回路和认知行为的变化的研究具有临床意义。最近的一项全基因组研究表明，当神经元兴奋时，一种称为eRNA（增强子RNA）的新型长非蛋白质编码RNA（lncRNA）会从数千个神经元增强子中快速表达。eRNA在各种类型的lncRNA中是非常独特的，因为它的表达是快速的，瞬时的，并且受感觉刺激诱发的神经元活动的动态控制。普遍的性质和强烈的表达相关性与附近的mRNA提出了一个发人深省的想法，eRNA可能在功能上涉及的感觉刺激诱导的神经和行为的可塑性，通过发挥积极的作用，在神经基因的表达。对eRNA功能的初步分析进一步支持了这一假设。鉴于少 哺乳动物基因组中蛋白质编码基因占2%以上，随着人类遗传学研究的不断深入，将发现越来越多与神经系统疾病相关的突变位于非编码区。这项研究涉及多学科的方法来研究eRNA在活性依赖性转录中的作用以及随后的突触和行为可塑性变化。依赖于eRNA的表观遗传机制可能代表了许多神经系统疾病分子结构中的一个新的复杂层。

DESCRIPTION (provided by applicant): A substantial body of evidence suggests that many neurological diseases may commonly result from perturbations of activity-dependent changes in neural functions. During brain development, sensory stimulation-dependent modulation of individual neurons and circuits involves not only structural and functional changes in local synaptic connections, but also a cell-wide arrangement for sustained adaptive responses. Sensory experience-dependent gene expression is an integral mechanism of cell-wide adaptation as it is responsible for the stimulus-specific production and deployment of proteins with various functions in individual neurons, which are required for appropriate adaptive responses. In keeping with this notion, mutations in several genes implicated in the signaling pathways from the synapse to the nucleus have been linked to various neurological diseases such as autism and epilepsy, suggesting that the disruption of activity-dependent gene expression programs under specific circumstances, such as activity-dependent learning can elicit a pathophysiological condition. As such, the study to understand how genetic and epigenetic programs accurately translate sensory information into changes in relevant neural circuits and cognitive behavior bears clinical significance. A recent genome-wide study revealed that a novel class of long non-protein coding RNAs (lncRNAs) called eRNAs (enhancer RNAs) is rapidly expressed from thousands of neuronal enhancers when neurons are excited. The eRNA is quite unique among various types of lncRNAs in that its expression is rapid, transient, and dynamically controlled by sensory stimulation-evoked neuronal activity. The pervasive nature and strong expression correlation with nearby mRNAs suggest a provoking idea that the eRNA might be functionally implicated in the sensory stimulation-induced neural and behavioral plasticity by playing an active role in neural gene expression. Initial analysis of the eRNA function further supports this hypothesis. Given that less than 2% of the mammalian genome accounts for protein-coding genes, an increasing number of mutations associated with neurological diseases will be found to reside in the non-coding regions as human genetic studies continue to advance. The proposed study involves a multidisciplinary approach to examine the role of eRNA in activity-dependent transcription and subsequent changes in synaptic and behavioral plasticity. The eRNA-dependent epigenetic mechanism may represent a new layer of complexity in the molecular architecture of many neurological diseases.