Epigenomic Modifications in Mammalian Neurogenesis

哺乳动物神经发生的表观基因组修饰

• 批准号: 8450219
• 负责人: QIANG LU
• 金额: $ 40.32万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450219
• 关键词: Acetylation; Address; Adult; Base Sequence; Behavioral; Biological Assay; Biological Markers; Birth; Brain; Brain Diseases; Cells; Cerebral cortex; Chromatin; Complex; Cytosine; DNA; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; Data; Development; Developmental Biology; Embryo; Ensure; Epigenetic Process; Equilibrium; Etiology; Event; Fathers; Future; Gene Expression; Gene-Modified; Genes; Genetic; Genomics; Global Change; Goals; Histones; Knowledge; Label; Lead; Location; Logic; Maps; Methods; Methylation; Modification; Mus; Neurons; Pattern; Polycomb; Process; Regenerative Medicine; Regulation; Reporter; Research; Role; Source; Specific qualifier value; Specificity; Stem cells; System; Validation; Work; cell fate specification; cell type; comparative; daughter cell; epigenome; epigenomics; genome wide association study; genome-wide; histone modification; improved; in vivo; innovation; insight; interest; malformation; nerve stem cell; neurodevelopment; neurogenesis; neuroregulation; novel; prospective; relating to nervous system; self-renewal; stem; tumor

DESCRIPTION (provided by applicant): The goal of this study is to understand how epigenomic modifications in neural stem/progenitor cells contribute to the control of a dynamic balance between the state of self-renewal and differentiation, a fundamental question of developmental biology that has a direct implication for improving our understanding of the mechanisms of brain development and the possible etiology of developmental or behavioral brain disorders. This will be done by characterizing the changes of global DNA and chromatin state during neurogenesis in brain development. Our approach will be aided by the development and validation of a novel genetic strategy for isolation of endogenous neural progenitor cells. In this genetic system, neural progenitor cells and their immediate neuronal progeny are differentially marked by the expression of two reporters, thereby allowing prospective co-isolation of these two cell types and providing an endogenous source of father- daughter cells suitable for comparative genome-wide epigenetic profiling. Using this genetic system, we will purify neural progenitor cells and progeny from the developing mouse cerebral cortex, characterize differential patterns of DNA methylation and histone modification between these two cell types, identify the marks that correlate with cell type-specific expression patterns of the modified genes, and explore the potential function of these marks in the regulation of cortical neurogenesis using established in vivo functional assays. We anticipate that this study will provide a comprehensive map of the epigenetic state of neural progenitor cells during neurogenesis, identify epigenetic marks potentially crucial for neural progenitor cell fate specification, as well as help identify pathological alterations in the epigenome which may lead to developmental and behavioral brain disorders.

描述（由申请人提供）：这项研究的目的是了解神经茎/祖细胞中的表观遗传学修饰如何有助于控制自我更新和分化状态之间的动态平衡，这是发育生物学的基本问题，这直接含义是我们对我们对大脑发育机制的理解以及可能的发展机构和发展性脑部障碍的理解。这将通过表征在脑发育中神经发生过程中整体DNA和染色质状态的变化来完成。我们的方法将通过开发和验证内源性神经祖细胞的新遗传策略的发展和验证。在这个遗传系统中，神经祖细胞及其直接神经元后代的表达差异化，从而允许这两种细胞类型的前瞻性共隔离，并提供适合于比较全基因组的父子子细胞的内源性来源。使用这种遗传系统，我们将从发育中的小鼠脑皮质中纯化神经祖细胞和后代，表征这两种细胞类型之间DNA甲基化的差异模式，并在这两种细胞类型之间进行了修改，并确定与修饰基因的细胞类型特异性表达模式相关的标记，并使用这些标记的consementional neurosementical sass sass instroundical sass inst of castorical sass sass inst sass inst of castorical sass inst of castorical sass inst of castors的函数。我们预计这项研究将为神经发生过程中神经祖细胞的表观遗传状态提供综合图，并确定对神经祖细胞命运规范至关重要的表观遗传标记，并有助于识别表观遗传组中的病理改变，这可能导致发育和行为脑部疾病。