Epigenetic Regulation of Peripheral Nerve Myelination

神经系统中轴突的髓鞘形成不仅对神经活动的传导至关重要 电位，但也提供趋向性支持，以确保神经元的长期存活 中枢和外周神经系统。髓鞘疾病是神经系统疾病的主要原因。 疾病，可由遗传疾病、传染病和炎症引起。 因此，了解髓鞘形成过程中控制基因表达模式的途径 细胞不仅是阐明发育途径的关键步骤，也是提供洞察力的关键一步 以加速神经损伤后的髓鞘再生。家蚕的遗传控制 髓鞘形成一直是研究的主要焦点，关键的转录因子及其靶点 基因网络已经开始被阐明。有趣的是，最近的研究表明 髓鞘的形成和长期维持不仅取决于基因 激活，但也下调了抑制髓鞘形成的基因。 尽管在识别基因表达变化方面取得了实质性进展，但 协调髓鞘形成，检测染色质的研究相对较少。 髓鞘形成所需的修饰。例如，髓鞘的维持依赖于 基因抑制程序，但关于组蛋白/DNA的作用几乎一无所知 甲基化在髓鞘形成的这一重要方面。我们实验室的长期目标是 从临界遗传和表观遗传阐明髓鞘形成的综合机制 髓鞘形成和维持所需的开关。具体地说，这项建议侧重于 检测多梳表观遗传通路在周围神经髓鞘形成中的作用。 染色质免疫沉淀分析将用于确定发育调节 表观遗传标记对损伤和衰老的反应。分析将集中在表观遗传学上。 在髓鞘形成过程中被抑制的基因位点发生的变化，并测试 多梳通路首次参与形成和长期维持 髓磷脂。最后，该方案还利用了外围设备的几个独特方面 神经，这促进了我们在这里提出的表观遗传学分析。

Myelination of axons in the nervous system is critical for not only conduction of action potentials, but also for providing tropic support to ensure long term survival of neurons in both the central and peripheral nervous systems. Myelin disorders are a major cause of neurological disease, and can be caused by genetic disorders, infectious disease, and inflammation. Therefore, understanding the pathways that control gene expression patterns in myelinating cells is a critical step in not only elucidating developmental pathways, but also to provide insight into means by which remyelination after nerve injury can be accelerated. The genetic control of myelination has been a major focus of research, and critical transcription factors and their target gene networks have begun to be elucidated. Interestingly, recent studies have demonstrated that formation of myelin¿and it longs term maintenance¿depends upon not only gene activation, but also downregulation of genes that inhibit myelin formation. Although substantial progress has been made to identify gene expression changes that coordinate myelination, there have been relatively few studies examining the chromatin modifications required for myelination. For example, myelin maintenance depends upon a program of gene repression, but practically nothing is known regarding the role of histone/DNA methylation in this vital aspect of myelination. The long term objective of our laboratory is to elucidate an integrated mechanism of myelination based on critical genetic and epigenetic switches required for myelin formation and maintenance. Specifically, this proposal focuses on testing the involvement of the polycomb epigenetic pathway in peripheral nerve myelination. Chromatin immunoprecipitation analyses will be used to determine the developmental regulation of epigenetic markers in response to injury and aging. The analysis will focus on epigenetic changes that occur in gene loci that are repressed during the myelination process, and test for the first time the involvement of the polycomb pathway in formation and long term maintenance of myelin. Finally, this proposal also takes advantage of several unique aspects of peripheral nerve, which facilitate the epigenetic analysis that we have proposed here.