Histone deacetylation in oligodendrocyte differentiation

描述（由申请人提供）：少突胶质细胞是中枢神经系统的髓磷脂形成细胞，对营养神经元支持至关重要。先前的研究表明，它们起源于谱系受限的同质祖细胞群体，然而一些报道对这一理论提出了挑战，并提出了不同祖细胞群体是否具有共同的少突胶质细胞分化分子机制的问题。在这个提议中，我们将检验假设，即所有少突胶质细胞祖细胞具有共同的表观遗传机制，即抑制髓鞘基因表达的转录抑制剂，神经元和星形细胞基因，这些基因需要组蛋白去乙酰化，并且是分化所必需的。根据我们的模型，祖细胞的一个共同特征是髓磷脂基因表达的高水平抑制剂，这是由于组蛋白乙酰化有利于启动子中染色质的转录活性构象。当祖细胞开始分化时，组蛋白去乙酰化（由hdac介导），使染色质转录失活，降低抑制剂水平，有利于髓磷脂基因表达。成熟的少突胶质细胞通过招募有利于染色质压实的蛋白质进一步沉默这些基因的表达。类似的机制被提出用于抑制神经元和星形细胞基因。该模型得到了大量初步结果和我们前期研究的支持。实验设计包括三个目的。目的1检验组蛋白去乙酰化是否为分化共同机制的一部分。另外两个目标定义了在少突胶质细胞分化过程中，负责抑制转录抑制剂（Aim 2）和神经元和星形细胞基因（Aim 3）的特定抑制复合物的作用。实验将在体外进行，使用培养的祖细胞，在体内进行，使用条件敲除小鼠和移植研究。这个模型代表了发育神经生物学领域概念上的进步，如果正确的话，将为治疗策略的发展提供重要的见解。因此，这项研究与公共卫生高度相关，因为它解决了对婴儿髓鞘发育异常和成人脱髓鞘修复至关重要的机制，并且因为多潜能胶质祖细胞的分化缺陷参与了胶质母细胞瘤的发生，胶质母细胞瘤是最常见和不可治疗的脑肿瘤形式。

DESCRIPTION (provided by applicant): Oligodendrocytes are the myelin-forming cells of the CNS and are essential for trophic neuronal support. Previous studies suggested that they originate from homogeneous population of lineage restricted progenitors, however several reports have challenged this theory and raised the question of whether distinct populations of progenitors may share a common molecular mechanism of oligodendrocyte differentiation. In this proposal we shall test the hypothesis that all oligodendrocyte progenitors share a common epigenetic mechanism of repression of transcriptional inhibitors of myelin gene expression, neuronal and astrocytic genes that requires histone deacetylation and is necessary for differentiation. According to our model, a common feature of the progenitors is the high levels of inhibitors of myelin gene expression, due to histone acetylation that favors a transcriptionally active conformation of the chromatin in their promoters. As the progenitors begin differentiating, histone deacetylation (mediated by HDACs),.renders the chromatin transcriptionally inactive, decreasing the levels of the inhibitors, and favoring myelin gene expression. Mature Oligodendrocytes further silence the expression of these genes by recruiting proteins that favor chromatin compaction. A similar mechanism is proposed for the repression of neuronal and astrocytic genes. This model is supported by a large amount of preliminary results and our previous studies. The experimental design consists of three aims. Aim 1 tests whether histone deacetylation is part of the common mechanism of differentiation. The other two aims define the role of specific repressive complexes responsible for the repression of transcriptional inhibitors (Aim 2), and of neuronal and astrocytic genes (Aim 3) during oligodendrocyte differentiation. The experiments will be performed in vitro, using cultured progenitors and in vivo, using conditional knockout mice and transplantation studies. This model represents a conceptual advance in the field of developmental neurobiology and, if correct, provides important insights for the development of therapeutic strategies. Therefore this study is highly relevant to public health because it addresses mechanisms that are critical for repair of dysmyelination in infants and demyelination in adults and because of the involvement of defective differentiation of multipotential glial progenitors in the genesis of glioblastomas, the most common and untreatable form of brain tumors.