Epigenetic Regulation of Peripheral Nerve Myelination

描述(申请人提供)：神经系统中轴突的髓鞘形成不仅对动作电位的传导至关重要，而且对提供趋向性支持以确保中枢和周围神经系统神经元的长期生存也是至关重要的。髓鞘疾病是神经系统疾病的主要原因，可由遗传疾病、传染病和炎症引起。因此，了解髓鞘细胞中控制基因表达模式的途径，不仅是阐明发育途径的关键一步，也是了解神经损伤后促进髓鞘再生的途径的关键一步。髓鞘形成的遗传控制一直是研究的重点，关键转录因子及其靶基因网络已开始被阐明。有趣的是，最近的研究表明，髓鞘的形成--以及它的长期维持--不仅取决于基因的激活，还取决于抑制髓鞘形成的基因的下调。尽管在识别协调髓鞘形成的基因表达变化方面已经取得了实质性的进展，但研究髓鞘形成所需的染色质修饰的研究相对较少。例如，髓鞘的维持依赖于基因抑制程序，但关于组蛋白/DNA甲基化在髓鞘形成的这一关键方面所起的作用，人们几乎一无所知。我们实验室的长期目标是阐明基于髓鞘形成和维持所需的关键遗传和表观遗传开关的髓鞘形成的完整机制。具体地说，这项建议侧重于测试多梳表观遗传途径在周围神经髓鞘形成中的参与。染色质免疫沉淀分析将被用来确定表观遗传标记对损伤和衰老的反应的发育调节。分析将集中在髓鞘形成过程中被抑制的基因座位上发生的表观遗传学变化，并首次测试多梳通路参与髓鞘的形成和长期维持。最后，这一建议还利用了周围神经的几个独特方面，这有助于我们在这里提出的表观遗传学分析。

DESCRIPTION (provided by applicant): 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.