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：
9327079
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 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9327079
关键词：
Adverse effects Alpha Cell Architecture Autistic Disorder Behavior 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 Regulation Gene Targeting Genes Genetic Genetic Transcription Genetic study High-Throughput Nucleotide Sequencing Hippocampus (Brain)Human Human Genetics Immediate-Early Genes Impairment Individual Label Learning Link Long-Term Potentiation Maintenance Mass Spectrum Analysis Memory Messenger RNA Methyl-CpG-Binding Protein 2 Modeling Molecular Mutation Names Nature Neuronal Plasticity 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 behavioral plasticity clinically significant cognitive function conditioned fear crosslinking and immunoprecipitation sequencing experience experimental study genome-wide genome-wide analysis insight interdisciplinary approach knock-down long term memory mRNA Expression mammalian genome memory consolidation memory process negative elongation factor nervous system disorder neural circuit neuroregulation novel overexpression programs promoter public health relevance relating to nervous system response spatiotemporal transcriptome

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可能是由神经功能活动依赖性变化的扰动引起的。在大脑发育过程中，单个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的安排。感觉体验依赖性基因表达是全细胞适应的一个不可或缺的机制，因为它负责在单个神经元中刺激特异性产生和部署具有各种功能的蛋白质，这是适当的适应性反应所必需的。根据这一观点，与从突触到细胞核的信号通路有关的几个基因的突变与各种神经系统疾病（例如自闭症和癫痫症）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，例如因为依赖活动的学习会引发病理生理状况。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，数千个神经元增强子会快速表达一类新型的长非蛋白编码 RNA (lncRNA)，称为 eRNA（增强子 RNA）。 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，并且受到感觉刺激诱发的神经元活动的动态控制。 eRNA 的普遍性和与附近 mRNA 的强烈表达相关性提出了一个令人兴奋的想法，即 eRNA 可能通过在神经基因表达中发挥积极作用，在功能上涉及感觉刺激诱导的神经和行为可塑性。对 eRNA 功能的初步分析进一步支持了这一假设。鉴于较少蛋白质编码基因占哺乳动物基因组的2%以上，随着人类遗传学研究的不断推进，越来越多的与神经系统疾病相关的突变将被发现存在于非编码区域。拟议的研究采用多学科方法来研究 eRNA 在活动依赖性转录中的作用以及突触和行为可塑性的后续变化。 eRNA 依赖性表观遗传机制可能代表了许多神经系统疾病分子结构中新的复杂性。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stimulus-specific combinatorial functionality of neuronal c-fos enhancers.

神经元 c-fos 增强剂的刺激特异性组合功能。

DOI：
发表时间：
2016-01
期刊：
影响因子：
25
作者：
Joo, Jae;Schaukowitch, Katie;Farbiak, Lukas;Kilaru, Gokhul;Kim, Tae
通讯作者：
Kim, Tae

PASNet: pathway-associated sparse deep neural network for prognosis prediction from high-throughput data.

PASNet：路径相关的稀疏深度神经网络，用于根据高通量数据进行预后预测。

DOI：
发表时间：
2018-12-17
期刊：
影响因子：
3
作者：
Hao, Jie;Kim, Youngsoon;Kim, Tae;Kang, Mingon
通讯作者：
Kang, Mingon

SET7/9 methylation of the pluripotency factor LIN28A is a nucleolar localization mechanism that blocks let-7 biogenesis in human ESCs.

多能因子 LIN28A 的 SET7/9 甲基化是一种核仁定位机制，可阻断人类 ESC 中 let-7 的生物合成。

DOI：
发表时间：
2014-12-04
期刊：
影响因子：
23.9
作者：
Kim, Seung;Lee, Hosuk;Han, Kyumin;Kim, Sang Cheol;Choi, Yoonjung;Park, Sang;Bak, Geunu;Lee, Younghoon;Choi, Jung Kyoon;Kim, Tae;Han, Yong;Lee, Daeyoup
通讯作者：
Lee, Daeyoup

Emerging themes in neuronal activity-dependent gene expression.

神经元活动依赖性基因表达的新主题。