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CNS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终末分化的机制。使用少突胶质细胞（OL）谱系作为模型系统，这个实验计划测试的假设，组蛋白去乙酰化是一个关键的事件，在这个过渡。所测试的模型是OL分化程序的“激活”通过由组蛋白去乙酰化介导的去阻遏机制发生。该模型意味着祖细胞通过“抑制”机制维持在未分化状态，该机制防止细胞骨架变化和成熟表型的基因表达特征模式。 向终末分化的过渡的特征在于由于组蛋白去乙酰化而解除这些机制的抑制。 具体目标1测试的假设，组蛋白脱乙酰化是必不可少的减少微管（即stathmin）和微丝（即凝溶胶蛋白）切断蛋白的表达，这是重要的终末分化的少突胶质细胞的形态学变化特征。 具体目标2测试的假设，组蛋白脱乙酰化有助于髓鞘基因的激活直接，通过压缩染色质在其启动子的负调控区。 特定目的3检验了以下假设：组蛋白去乙酰化通过调节编码抑制性分子的基因的启动子区域中的染色质致密化而间接地有助于髓磷脂基因表达的激活。 这些研究的结果有望对目前基因表达的发育调控概念以及多发性硬化症和CNS损伤后的髓鞘再生治疗产生广泛的影响。此外，通过解决其表达在神经胶质肿瘤中改变的基因的调节，它们可能有助于神经胶质祖细胞的肿瘤转化的一般知识。

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.