Epigenetic regulation of neurogenesis

摘要 中枢神经系统的发育需要几个调节系统之间协调的相互作用。 决定细胞在任何给定时间的命运、性质和功能的元素，最终导致 控制我们最基本行为和复杂认知过程的复杂神经网络。作为 DNA序列和基因表达之间的中间调节结构域，表观遗传机制可以 对大脑发育产生了相当大的影响，我们才刚刚开始意识到这一点。一 近年来表观遗传学领域的主要进展是发现了基因组的新修饰， DNA，如5-羟甲基胞嘧啶（5 hmC），以及安装，移除和解释这些的分子途径 修饰，其在神经系统中高度富集，并由神经元动态调节。 在生理和病理条件下的活性。本P01的总体目标是 了解表观基因组和转录组的全球和特定变化的系统方法 利用海马神经发生调节干细胞行为、神经元发育和神经元整合 作为一个模型系统。 海马神经发生是成年哺乳动物脑中的组成性现象，并且是一个良好的- 建立了神经发育的模型，该模型由起源于神经干的定义阶段组成 细胞激活，并导致解剖学上单一神经元亚型的成熟和整合。 大脑的限制区域。这种现象也代表了惊人的结构可塑性， 显示有助于关键的大脑功能，而其失调已被牵连在各种 神经和退行性疾病。海马神经源性过程的特征可能 最终为基于细胞移植的治疗策略提供信息，以修复中枢神经系统， 中风、损伤或神经系统疾病。 整合啮齿类动物成年海马神经发生与人类诱导多能干细胞的结果 细胞（iPSC）为基础的模型将允许确定基本的表观遗传原则， 在分子、细胞和系统水平上的发展。我们的团队包括表观遗传学专家， 海马神经发生，啮齿动物干细胞生物学，人iPSCs，化学生物学，高通量 测序、生物信息学、电生理学和移植。成功完成研究 这些项目将指导未来对神经发育中失调的DNA修饰作用的研究。 疾病和促进新的技术方法的发展，以确定表观遗传标记， 高分辨率。

ABSTRACT Development of the central nervous system requires orchestrated interactions among several regulatory elements that determine the fate, properties, and functions of cells at any given time, ultimately leading to complex neural networks that control our most basic behaviors and complex cognitive processes. As an intermediate regulatory domain between DNA sequences and gene expression, epigenetic mechanisms can exert considerable influence on brain development on a scale that we are only beginning to appreciate. One major advance in the field of epigenetics in recent years is the discovery of novel modifications of genomic DNA, such as 5-hydroxymethylcytosine (5hmC), and molecular pathways to install, remove, and interpret these modifications, which are highly enriched in the nervous system and are dynamically regulated by neuronal activity under physiological and pathological conditions. The overarching goal of this P01 is to take a systematic approach to understand how global and specific changes in the epigenome and transcriptome regulate stem cell behavior, neuronal development and neuronal integration using hippocampal neurogenesis as a model system. Hippocampal neurogenesis is a constitutive phenomenon in the adult mammalian brain and is a well- established model for neural development that is comprised of defined stages, which originate with neural stem cell activation and result in the maturation and integration of a single neuronal subtype in an anatomically restricted region of the brain. This phenomenon also represents striking structural plasticity and has been shown to contribute to critical brain functions, whereas its dysregulation has been implicated in various neurological and degenerative disorders. Characterization of neurogenic processes in hippocampus may eventually inform cell transplantation-based therapeutic strategies to repair the central nervous system after stroke, injury or neurological disorders. Integrating results from adult hippocampal neurogenesis in rodents with human induced pluripotent stem cell (iPSC)-based models will allow for the identification of fundamental epigenetic principles governing neural development at the molecular, cellular, and systems levels. Our team includes experts in epigenetics, hippocampal neurogenesis, rodent stem cell biology, human iPSCs, chemical biology, high-throughput sequencing, bioinformatics, electrophysiology and transplantation. Successful completion of the research projects will guide future investigations into the role of dysregulated DNA modifications in neurodevelopmental disorders and facilitate the development of new technological approaches to identify epigenetic marks with high resolution.