The epigenetic mechanism of enhancer RNA in behavioral plasticity

增强子RNA在行为可塑性中的表观遗传机制

基本信息

批准号：
8893181
负责人：
Tae-Kyung Kim
金额：
$ 34.78万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8893181
关键词：
Accounting Adverse effects Architecture Autistic Disorder Behavior Behavioral Binding Biochemical Biological Assay Biological Models Brain Cell Nucleus Cells Co-Immunoprecipitations Code Cognitive Complex Development Elongation Factor Enhancers Epigenetic Process Epilepsy Exhibits FOS gene Fluorescent in Situ Hybridization Functional disorder Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genetic study Health High-Throughput Nucleotide Sequencing Hippocampus (Brain)Human Human Genetics Immediate-Early Genes Individual Label Learning Link Long-Term Potentiation Maintenance Mass Spectrum Analysis Memory Messenger RNA Modeling Molecular Mutation Names Nature Neurons Neurophysiology - biologic function Pathway interactions Phase Play Production Proteins RNA RNA Polymerase II RNA Sequences RNA chemical synthesis Regulation Rett Syndrome Role Rubinstein-Taybi Syndrome Sensory Signal Pathway Signal Transduction Slice Source Stimulus Synapses Synaptic plasticity Testing Translating Untranslated RNA Ursidae Family base clinically significant cognitive function conditioned fear experience genome-wide genome-wide analysis insight interdisciplinary approach long term memory mRNA Expression mammalian genome memory consolidation memory process negative elongation factor nervous system disorder neural circuit neuroregulation novel overexpression programs promoter relating to nervous system research study response spatiotemporal transcriptome sequencing

项目摘要

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.

描述（由申请人提供）：大量证据表明，许多神经系统疾病通常是由于神经功能的活动依赖性变化而引起的。在大脑发育过程中，感官刺激依赖性调节单个神经元和电路不仅涉及局部突触连接的结构和功能变化，而且还涉及用于持续适应性反应的细胞整体排列。感官经验依赖性基因表达是细胞范围适应的一种组成机制，因为它负责具有各种神经元中具有各种功能的蛋白质的刺激特异性产生和部署，这是适当的自适应反应所必需的。与这个概念保持一致，几个基因的突变与从突触到核的信号传导途径有关，与各种神经系统疾病（如自闭症和癫痫病）有关，这表明在特定情况下，诸如活动依赖性学习等特定情况下的活动依赖性基因表达程序的破坏会导致病理生理学疾病。因此，该研究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的变化和认知行为的变化具有临床意义。一项全基因组的一项研究表明，当神经元激发神经元时，一类新型的非蛋白质编码RNA（LNCRNA）称为ERNAS（增强剂RNA），它迅速从数千个神经元增强剂中表达。 ERNA在各种类型的LNCRNA中非常独特，因为它的表达是快速，短暂的，并且通过感觉刺激引起的神经元活性动态控制。普遍的性质和与附近mRNA的强烈表达相关性表明，通过在神经基因表达中发挥积极作用，可以在功能上与感觉刺激诱导的神经和行为可塑性有关。 ERNA功能的初始分析进一步支持了这一假设。给出少的超过2％的哺乳动物基因组解释了蛋白质编码基因，随着人类遗传研究的继续前进，与神经系统疾病相关的突变数量越来越多。拟议的研究涉及一种多学科方法，以检查ERNA在活动依赖性转录以及随后的突触可塑性变化中的作用。依赖ERNA的表观遗传机制可能代表了许多神经系统疾病的分子结构中的新复杂性。