Histone deacetylation in oligodendrocyte differentiation

描述（由申请人提供）：本研究计划的长期目标是了解中枢神经系统祖细胞分化的发育机制。更具体地说，这项资助的重点是阐明负责从晚期祖细胞阶段过渡到末期分化的机制。利用少突胶质细胞（OL）谱系作为模型系统，本实验计划验证了组蛋白去乙酰化是这一转变过程中的关键事件的假设。正在测试的模型是通过组蛋白去乙酰化介导的去抑制机制来“激活”OL分化程序。该模型表明，祖细胞通过“抑制”机制维持在未分化状态，阻止细胞骨架变化和成熟表型特征的基因表达模式。过渡到终端分化的特征是由于组蛋白去乙酰化导致这些机制的去抑制。特异性目的1验证了组蛋白去乙酰化对于降低微管（即stathmin）和微丝（即gelsolin）切断蛋白的表达至关重要的假设，而微管（即stathmin）和微丝（即gelsolin）切断蛋白对于终分化少突胶质细胞的形态变化特征至关重要。特异性目的2验证了组蛋白去乙酰化通过紧致启动子负调控区域的染色质直接促进髓磷脂基因激活的假设。特异性Aim 3验证了组蛋白去乙酰化通过调节编码抑制分子的基因启动子区域的染色质压实间接促进髓磷脂基因表达激活的假设。这些研究的结果有望对当前基因表达发育调控的概念以及多发性硬化症和中枢神经系统损伤后的再髓鞘化治疗产生广泛的影响。此外，通过解决神经胶质肿瘤中表达改变的基因调控，它们可能有助于了解神经胶质祖细胞的肿瘤转化。

DESCRIPTION (provided by applicant): The long-term goal of this research proposal is to understand the developmental mechanisms of CNS progenitor differentiation. More specifically the focus of this grant is to elucidate the mechanisms responsible for the transition from the late progenitor stage to terminal differentiation. Using the oligodendrocyte (OL) lineage as model system, this experimental plan tests the hypothesis that histone deacetylation is a crucial event during this transition. The model being tested is that "activation" of the OL differentiation program occurs through a de-repression mechanism, mediated by histone deacetylation. This model implies that progenitors are maintained in an undifferentiated state by "inhibitory" mechanisms that prevent the cytoskeletal changes and the pattern of gene expression characteristic of the mature phenotype. The transition to terminal differentiation is characterized by disinhibition of these mechanisms due to histone deacetylation. Specific Aim 1 tests the hypothesis that histone deacetylation is essential for decreasing the expression of microtubule (i.e. stathmin) and microfilament (i.e. gelsolin) severing proteins which are important for the morphological changes characteristic of terminally differentiated oligodendrocytes. Specific Aim 2 tests the hypothesis that histone deacetylation contributes to the myelin gene activation DIRECTLY, by compacting chromatin in the negative regulatory regions of their promoters. Specific Aim 3 tests the hypothesis that histone deacetylation contributes to activation of myelin gene expression INDIRECTLY, by regulating chromatin compaction in the promoter region of genes encoding inhibitory molecules. The results of these studies are expected to have broad implications for the current concept of developmental regulation of gene expression and also for remyelination therapies in multiple sclerosis and after CNS injury. Furthermore, by addressing the regulation of genes whose expression is altered in glial tumors, they may contribute to the general knowledge of neoplastic transformation of glial progenitor.