Molecular determinants of oligodendrocyte differentiation and myelination

少突胶质细胞是中枢神经系统的髓鞘胶质细胞。这些细胞延伸出许多突起，将神经元轴突包裹在一个紧密的膜鞘中。髓鞘允许快速、有效的神经传递，这对协调运动和更高的认知功能都很重要。出生后早期发育是大脑中髓鞘形成最强烈的时期。在此期间，干细胞经历了几个不同的阶段，在皮质和底层白质中迁移，达到成熟的髓鞘表型。通过这些阶段的进展是由调控基因表达的转录网络控制的。虽然我们对参与少突胶质细胞发生的单个转录因子的了解在继续扩大，但最终这些需要在更广泛的调控网络的背景下加以考虑。一些表观遗传修饰物，包括组蛋白乙酰转移酶(HATS)和组蛋白脱乙酰基酶(HDACs)，调节染色质的可及性来调节转录。我对NSERC资助的研究项目的长期愿景是定义调控发育髓鞘形成的分子参与者和相互作用网络。在这个最初的研究方案中，我的团队将致力于系统地确定HATS和HDAC在少突胶质前体细胞增殖和分化中的作用。我们将表征乙酰基转移酶和脱乙酰基酶在分化的每个阶段的表达水平和亚细胞位置，以确定寡突发生的关键调控因素。综合基因组和蛋白质组学方法将被用来识别调节基因表达的转录复合体，为本科生和研究生提供严格的、尖端的培训环境。乙酰基转移酶和脱乙酰基酶都通过修饰组蛋白和其他靶蛋白(包括转录因子)来发挥作用，这表明了这些翻译后修饰在调节细胞功能方面的重要性。关于其中许多酶在细胞分化中的具体作用，如它们如何针对基因组的不同区域，以及不同类别之间功能重叠的程度，人们知之甚少。因此，我的研究计划将有助于从根本上理解转录因子和表观遗传修饰物的协调作用如何导致发育中的大脑中高度协调和严格调控的基因表达。

Oligodendrocytes are the myelinating glia of the central nervous system. These cells extend numerous processes that wrap the neuronal axons in a compact membranous sheath. The myelin sheath allows for fast, efficient neurotransmission, which is important for both coordinated movement and higher cognitive functions. Early postnatal development is the most intense period of myelination in the brain. During this time, stem cells undergo changes through several distinct stages, migrating throughout the cortex and underlying white matter to reach a mature, myelinating phenotype. Progress through these stages is governed by transcriptional networks regulating gene expression. While our knowledge of individual transcription factors that are involved in oligodendrogenesis continues to expand, ultimately these need to be considered in the context of a broader regulatory network. Several epigenetic modifiers, including histone acetyltransferases (HATs) and histone deacetylases (HDACs), modulate the accessibility of chromatin to regulate transcription. My long-term vision for a NSERC-funded research program is to define the molecular players and interaction networks that regulate developmental myelination. In this initial research proposal, my team will work to systematically define the role of HATs and HDACs in the proliferation and differentiation of oligodendrocyte progenitor cells. We will characterize the expression levels and subcellular location of acetyltransferases and deacetylases during each stage of differentiation to determine key regulators of oligodendrogenesis. Integrated genomic and proteomic approaches will be employed to identify transcriptional complexes regulating gene expression providing a rigorous, cutting-edge training environment for undergraduate and graduate students. The emerging role of acetyltransferases and deacetylases, both through modification of histones and other target proteins (including transcription factors), signifies the importance of these post-translational modifications in regulating cellular function. Relatively little is known regarding the specific roles of many of these enzymes in cell differentiation, such as how they are targeted to different regions of the genome and the extent of overlap of function between the different classes. Thus, my research program will contribute to the fundamental understanding of how the coordinated actions of transcription factors and epigenetic modifiers lead to the highly orchestrated and tightly regulated gene expression in the developing brain.