The histone code of neuronal function and dysfunction

项目摘要 神经科学领域的一个根本挑战是理解环境信号之间的联系 以及导致神经元功能长期变化的转录反应。神经元 唯一需要对基因激活进行高度动态和时间控制的过程，从记忆 在发育过程中形成突触。特定的基因是否最终被激活是非常重要的 依赖于通过控制DNA的组蛋白对转录的表观遗传调节 可获得性和调节转录。这种‘组蛋白密码’的重要性正变得越来越重要 在神经科学中受到赞赏，从它在记忆存储中的功能到它参与神经疾病。 我的目标是阐明控制神经系统的组蛋白密码，目的是更好地理解 转录调控在正常神经元以及精神和发育障碍中的转录调节这个 我建议的研究涵盖了组蛋白调控的所有方面，并在工作中有坚实的基础 在Allis实验室开发和执行组蛋白修饰和变体。在培训期间 期间，我将继续研究组蛋白失调在神经发育障碍中的作用以及 以此为靶点以减轻神经元功能障碍的可能性。我还将调查一个新发现的角色 组蛋白变异体与突触活动的转录反应有关。最后，我将开始调查 组蛋白修饰的作用，如巴豆化，尚未被研究的背景神经元基因 表达，但提供实现不同功能所需的复杂转录调控 神经系统。在这段指导期内，我建议开发和扩展我将使用的新工具 在颁奖的独立阶段。此外，我还将学习计算和计算的结合 基因组学技术和生化方法将使我脱颖而出，并为我提供 在表观遗传学和神经科学的交叉点工作所需的技能。随着新技术的发展 我在培训奖励计划中描述的工具和获得的有价值的技能，我将是一个独特的职位 应用不同的方法揭示组蛋白在基因转录调控中的作用 对神经功能至关重要。这项研究将使基因激活的组蛋白密码应用于 大脑中的信息存储，为神经元功能的潜在机制和 神经性疾病的表观遗传原因。

Project Summary A fundamental challenge in the field of neuroscience is understanding the link between environmental signals and the transcriptional response underlying the resulting long term changes in neuronal function. Neurons uniquely require highly dynamic and temporal control of gene activation for processes ranging from memory formation to synapse formation during development. Whether specific genes are ultimately activated is highly dependent on the epigenetic regulation of transcription through the histone proteins that control DNA accessibility and regulate transcription. The importance of this `histone code' or is becoming increasingly appreciated in neuroscience, from its function in memory storage to its involvement in neurological disorders. My goal is to elucidate the histone code that controls the nervous system with the aim of better understanding the regulation of transcription both in normal neurons and in mental and developmental disorders. The research I propose encompasses all aspects of histone regulation and has a strong foundation in the work developed and performed in the Allis laboratory on histone modifications and variants. During the training period, I will continue my work on the role of histone misregulation in neurodevelopmental disorders and the possibility of targeting this to alleviate neuronal dysfunction. I will also investigate the role of a new discovered histone variant linked to the transcriptional response to synaptic activity. Finally, I will begin to investigate the role of histone modifications such as crotonylation that have not yet been examined the context neuronal gene expression but provide the complex transcriptional regulation needed to achieve the varied functions of the nervous system. During this mentored period, I propose to develop and expand on new tools I will use to during the independent phase of the award. In addition, I will learn a combination of computational and genomics techniques and biochemical approaches that will set me apart from the field and provide me with the skills necessary to work at the intersection of epigenetics and neuroscience. With the development of new tools and acquisition of valuable skills that I describe in the training plan of award, I will be a unique position to apply diverse approaches to reveal new insights into the role of histones in regulating transcription of genes critical for neuronal function. This research will allow for the histone code of gene activation to be applied to information storage in the brain, providing new insights into mechanism underlying neuronal function and the epigenetic causes of neurological disorders.