Epigenetic Regulation of Peripheral Nerve Myelination

周围神经髓鞘形成的表观遗传调控

• 批准号: 8575660
• 负责人: John P Svaren
• 金额: $ 3.15万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8575660
• 关键词: Action Potentials; Affect; Aging; Axon; Cells; ChIP-seq; Charcot-Marie-Tooth Disease; Chromatin Remodeling Factor; Communicable Diseases; Complex; DNA Methylation; Data; Deacetylase; Development; Diabetic Neuropathies; Disease; Down-Regulation; Effectiveness; Ensure; Epigenetic Process; Gene Activation; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic; Goals; Hereditary Disease; Histone H3; Histones; Inflammation; Injury; Laboratories; Maintenance; Maps; Methylation; Modification; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; Nerve; Nervous System Trauma; Nervous system structure; Neurons; Nucleosomes; Pathway interactions; Peripheral; Peripheral Nerves; Peripheral Nervous System; Polycomb; Process; Recovery; Regulation; Repression; Research; Role; Schwann Cells; Sequence Analysis; Site; Techniques; Testing; Time; Transcription factor genes; Transcriptional Regulation; base; chromatin immunoprecipitation; chromatin modification; epigenetic marker; gene repression; genome-wide; histone modification; in vivo; insight; myelination; nerve injury; nervous system development; nervous system disorder; normal aging; programs; remyelination; research study; response; response to injury; transcription factor

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.

神经系统中轴突的髓鞘化不仅对行为的传导至关重要， 潜力，但也提供热带支持，以确保长期生存的神经元在这两个 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，并且可以由遗传疾病、传染病和炎症引起。 因此，了解控制髓鞘形成中基因表达模式的途径， 细胞不仅是阐明发育途径的关键一步， 从而加速神经损伤后髓鞘再生。的遗传控制 髓鞘形成一直是研究的主要焦点，并且关键转录因子及其靶点 基因网络已经开始被阐明。有趣的是，最近的研究表明， 髓磷脂的形成及其长期维持不仅取决于基因， 激活，但也下调抑制髓鞘形成的基因。 尽管在鉴定基因表达变化方面已经取得了实质性进展， 协调髓鞘形成，有相对较少的研究检查染色质 髓鞘形成所需的修饰。例如，髓磷脂的维持依赖于 基因抑制的程序，但实际上是什么都不知道关于组蛋白/DNA的作用 甲基化在髓鞘形成的这个重要方面。我们实验室的长期目标是 阐明髓鞘形成的综合机制，基于关键的遗传和表观遗传 髓鞘形成和维持所需的开关。具体而言，该提案侧重于 测试外周神经髓鞘形成中多梳表观遗传途径的参与。 染色质免疫沉淀分析将用于确定发育调控 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 在髓鞘形成过程中受到抑制的基因位点发生的变化，并检测 这是首次发现多梳状通路参与形成和长期维持， 髓磷脂最后，该建议还利用了外围设备的几个独特方面， 神经，这有助于我们在这里提出的表观遗传分析。