Histone deacetylation in oligodendrocyte differentiation

描述(申请人提供)：本研究方案的长期目标是了解中枢神经系统前体细胞分化的发育机制。更具体地说，这笔赠款的重点是阐明从晚期祖细胞阶段向终末分化阶段过渡的机制。使用少突胶质细胞(OL)谱系作为模型系统，本实验计划验证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，OL分化程序的“激活”是通过组蛋白去乙酰化介导的去抑制机制发生的。这一模型表明，通过阻止细胞骨架变化和成熟表型特有的基因表达模式，祖细胞保持在未分化状态。向终末分化的转变特征是由于组蛋白去乙酰化而使这些机制不受抑制。特异性目标1验证了组蛋白去乙酰化对于减少微管(即stathmin)和微丝(即明胶蛋白)切割蛋白的表达至关重要的假说，这两种蛋白对于终末分化的少突胶质细胞的形态变化是重要的。特异性目标2验证了组蛋白去乙酰化通过压缩其启动子负调控区域的染色质而直接促进髓鞘基因激活的假说。特异靶3验证组蛋白脱乙酰化通过调节抑制分子基因启动子区域的染色质紧凑，间接促进髓鞘基因表达的激活。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髓鞘再分化治疗具有广泛的意义。此外，通过对胶质瘤中表达改变的基因的调控，他们可能有助于了解神经胶质前体细胞的肿瘤性转化。

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.