Neuronal Epigenomic Changes in Neurodevelopment and Disease

神经发育和疾病中的神经元表观基因组变化

基本信息

批准号：
8327141
负责人：
MICHAEL ELDON GREENBERG
金额：
$ 41.32万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8327141
关键词：
Address Behavior Behavioral Brain Cell Count Cell Nucleus Cells Chromatin Chromatin Structure Code Cognitive Complement DNA DNA Methylation DNA Methylation Regulation Data Development Disease Environment Epigenetic Process Evaluation Event Fluorescence-Activated Cell Sorting Gene Expression Genes Genetic Genomics Histones Investigation Laboratories Life Life Experience Maps Mediating Mental disorders Methods Methylation Modification Molecular Nature Neuraxis Neurodevelopmental Disorder Neuronal Plasticity Neurons Neurophysiology - biologic function Nucleic Acid Regulatory Sequences Physiological Physiology Population Post-Translational Protein Processing Process Regulation Risk Role Source Staging Stimulus Structure System Techniques Tissues base cell type epigenomics experience genome wide association study genome-wide genome-wide analysis hippocampal pyramidal neuron in vivo insight neocortical neurodevelopment next generation novel strategies programs relating to nervous system research study response success

项目摘要

DESCRIPTION (provided by applicant): Early-life experiential and environmental conditions, particularly those occurring during heightened periods of brain plasticity, are known to promote long-term changes in physiology and behavior that act independently of changes in the DNA code. Accumulating evidence suggests an important role for epigenomic processes in these epigenetic phenomena. In particular, recent data from a variety of sources suggest that experience-dependent changes in DNA methylation can have a long-lasting impact on neural function through sustained effects on neuronal gene expression. However, the fact that these modifications occur in vivo in a relatively small number of cells within highly heterogeneous neural tissue limits the study of these modifications with existing genomic approaches and greatly complicates investigation of the underlying molecular mechanisms. We propose a two-pronged approach to begin to address these issues. First, we will pursue a reductionist approach to the study of experience-driven changes in DNA methylation, employing a dissociated neuronal culture system that shows activity-induced changes in DNA methylation and in which a large number of cells can be synchronously activated with robust stimuli. Moreover, to complement and address limitations inherent in this reductionist approach, we have also developed a general genetic strategy to specifically isolate chromatin from defined cell types in vivo, enabling the analysis of DNA methylation changes induced in specific neuronal cell populations in response to early-life experiences using massively parallel sequencing techniques. Thus, we propose: 1) To employ a dissociated neuronal culture system to characterize neuronal activity-induced changes in DNA methylation, and 2) To investigate long-lasting neuronal epigenomic correlates to experience-driven behavioral and physiological changes in vivo. It is our hope that the proposed experiments will establish new approaches for the analysis of neuronal epigenomic modifications, advance our understanding of the regulation of DNA methylation in the developing central nervous system, and ultimately provide new insights into the importance of these mechanisms for neurodevelopment, cognitive behavior, and disease.

描述（由申请人提供）：已知生命早期的经历和环境条件，特别是在大脑可塑性增强时期发生的条件，会促进生理和行为的长期变化，而这些变化独立于 DNA 密码的变化。越来越多的证据表明表观基因组过程在这些表观遗传现象中发挥着重要作用。特别是，最近来自各种来源的数据表明，DNA 甲基化的依赖于经验的变化可以通过对神经元基因表达的持续影响，对神经功能产生持久的影响。然而，这些修饰在体内发生在高度异质性神经组织内相对较少数量的细胞中，这一事实限制了用现有基因组方法对这些修饰的研究，并使潜在分子机制的研究变得非常复杂。我们建议采取双管齐下的方法来开始解决这些问题。首先，我们将采用还原论方法来研究经验驱动的 DNA 甲基化变化，采用分离的神经元培养系统，该系统显示活动诱导的 DNA 甲基化变化，并且在强刺激下可以同步激活大量细胞。此外，为了补充和解决这种还原论方法固有的局限性，我们还开发了一种通用遗传策略，可以从体内特定的细胞类型中特异性分离染色质，从而能够分析特定神经元细胞群中响应早期反应而诱导的 DNA 甲基化变化。使用大规模并行测序技术的生活经历。因此，我们建议：1）采用分离的神经元培养系统来表征神经元活动引起的 DNA 甲基化变化，2）研究持久的神经元表观基因组与体内经验驱动的行为和生理变化的相关性。我们希望所提出的实验能够建立分析神经元表观基因组修饰的新方法，增进我们对发育中的中枢神经系统中DNA甲基化调节的理解，并最终为这些机制对神经发育的重要性提供新的见解。认知行为和疾病。