Epigenetic regulation of neurogenesis

摘要 中枢神经系统的发展需要几个调节因素之间的协调相互作用 在任何给定时间决定细胞命运、属性和功能的元素，最终导致 控制我们最基本的行为和复杂的认知过程的复杂神经网络。作为一种 DNA序列和基因表达之间的中间调节域，表观遗传机制可以 对大脑发育产生相当大的影响，其规模我们才刚刚开始欣赏。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(5HmC)，以及安装、移除和解释这些的分子途径 修饰，在神经系统中高度丰富，并由神经元动态调节 生理和病理条件下的活动。这个P01的首要目标是用一个 用系统的方法了解表观基因组和转录组的全局和特定变化 利用海马神经发生调控干细胞行为、神经元发育和神经元整合 作为一个模范系统。 海马神经发生是成年哺乳动物大脑中的一种结构性现象，是一种良好的神经发生机制。 建立了神经发育的模型，该模型由定义的阶段组成，这些阶段源于神经干细胞 细胞激活并导致单个神经元亚型在解剖学上的成熟和整合 大脑的受限区域。这一现象也代表了惊人的结构可塑性，并已 被证明对关键的大脑功能有贡献，而它的失调涉及到各种 神经和退行性疾病。海马区神经发生过程的特征可能 最终告知以细胞移植为基础的修复中枢神经系统后的治疗策略 中风、损伤或神经功能障碍。 用人诱导的多能干细胞整合成年啮齿动物海马神经发生的结果 基于细胞(IPSC)的模型将允许识别支配神经的基本表观遗传原理 在分子、细胞和系统层面上的发展。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，人类ipscs，化学生物学，高通量 测序、生物信息学、电生理学和移植。顺利完成研究工作 这些项目将指导未来对失调的DNA修饰在神经发育中的作用的研究 并促进开发新的技术方法，以识别表观遗传标记 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.