The epigenetic mechanism of enhancer RNA in behavioral plasticity

描述(由申请人提供)： 大量证据表明，许多神经疾病通常是由于依赖活动的神经功能变化的扰动造成的。在大脑发育过程中，依赖感觉刺激的单个神经元和回路的调制不仅涉及局部突触连接的结构和功能变化，而且还涉及到整个细胞范围内持续适应性反应的安排。感觉经验依赖的基因表达是整个细胞适应的一个完整机制，因为它负责刺激特异性地在单个神经元中产生和部署具有不同功能的蛋白质，这些蛋白质是适当的适应反应所必需的。与这一概念一致的是，从突触到核的信号通路中涉及的几个基因的突变与各种神经疾病有关，如自闭症和癫痫，这表明在特定情况下，活动依赖的基因表达程序的中断，如活动依赖的学习，可能会引发病理生理状况。因此，了解遗传和表观遗传程序如何将感觉信息准确地转化为相关神经回路和认知行为的变化具有临床意义。最近的一项全基因组研究表明，当神经元兴奋时，数千个神经元增强子迅速表达一类新的长非蛋白编码RNA(LncRNAs)，称为eRNAs(增强子RNAs)。在各种类型的lncRNA中，Erna是非常独特的，因为它的表达是快速、瞬时的，并且受感觉刺激诱发的神经元活动的动态控制。这种普遍存在的性质和与邻近mRNAs的强表达相关性表明，Erna可能通过在神经基因表达中发挥积极作用，在感觉刺激诱导的神经和行为可塑性中发挥作用。对Erna函数的初步分析进一步支持了这一假设。考虑到这一点 随着人类遗传学研究的不断深入，随着人类遗传学研究的不断深入，越来越多的与神经系统疾病相关的突变将被发现驻留在非编码区。这项拟议的研究涉及一种多学科的方法来研究Erna在活性依赖的转录以及随后的突触和行为可塑性变化中的作用。ERNA依赖的表观遗传机制可能代表了许多神经疾病的分子结构中新的一层复杂性。

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.