The Histone Code of Neuronal Function and Dysfunction

项目总结： 神经科学领域的一个根本挑战是理解环境信号和导致神经元功能长期变化的转录反应之间的联系。神经元在发育过程中需要对从记忆形成到突触形成的过程进行高度动态和时间上的基因激活控制。特定基因是否最终被激活高度依赖于通过控制DNA可及性和调节转录的组蛋白对转录的表观遗传调节。这种“组蛋白密码”的重要性在神经科学中越来越受到重视，从它在记忆存储中的功能，到它在神经疾病中的作用。我的目标是阐明控制神经系统的组蛋白密码，目的是更好地了解正常神经元以及精神和发育障碍中的转录调节。我建议的研究涵盖了组蛋白生物学的所有方面，包括组蛋白结合蛋白、组蛋白修饰和组蛋白变体。我将在我博士后工作的基础上，继续检索组蛋白失调在神经发育障碍中的作用，以及以此为靶点缓解神经元功能障碍的可能性。我还将继续研究一种新发现的与突触活动的转录反应有关的组蛋白变体的作用。最后，我将检验组蛋白修饰的作用，如巴豆化，这还没有被研究背景神经元基因表达，但提供实现神经系统的各种功能所需的复杂转录调节。我将把我在培训中学到的工具和技能应用到神经科学的研究中。从生化方法到计算和基因组学技术，这些技能将使我在这个领域脱颖而出，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背景。随着我作为独立研究员开始我的工作，我将成为一个独特的职位，应用不同的方法来揭示组蛋白在调节神经功能关键基因转录方面的作用。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，为神经功能潜在的机制和神经疾病的表观遗传原因提供新的见解。

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 biology including histone binding proteins, histone modifications, and histone variants. I will build on my postdoctoral work by continuing to examine on the role of histone misregulation in neurodevelopmental disorders and the possibility of targeting this to alleviate neuronal dysfunction. I will also continue my investigation into the role of a new discovered histone variant linked to the transcriptional response to synaptic activity. Finally, I will examine 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. I will apply the tools and skills I learned during my training to the study of neuroscience. These skills ranging from biochemical approaches to computational and genomics techniques will set me apart from the field and provide me with the background necessary to work at the intersection of epigenetics and neuroscience. As I begin my work as independent investigator, 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.