Histone deacetylation in oligodendrocyte differentiation

描述（由申请方提供）：少突胶质细胞是CNS的髓鞘形成细胞，对营养神经元支持至关重要。以前的研究表明，它们起源于谱系限制的祖细胞的同质群体，然而，一些报告挑战了这一理论，并提出了一个问题，即不同的祖细胞群体是否可能具有共同的少突胶质细胞分化的分子机制。在这个建议中，我们将测试的假设，所有少突胶质细胞祖细胞共享一个共同的表观遗传机制的抑制髓磷脂基因表达的转录抑制因子，神经元和星形胶质细胞基因，需要组蛋白脱乙酰化，是必要的分化。根据我们的模型，祖细胞的一个共同特征是髓鞘基因表达的高水平抑制剂，这是由于组蛋白乙酰化有利于其启动子中染色质的转录活性构象。随着祖细胞开始分化，组蛋白脱乙酰化（由HDAC介导）使染色质转录失活，降低抑制剂的水平，并有利于髓磷脂基因表达。成熟的少突胶质细胞通过募集有利于染色质致密化的蛋白质来进一步沉默这些基因的表达。神经元和星形胶质细胞基因的抑制也有类似的机制。该模型得到了大量的初步结果和我们以前的研究的支持。实验设计包括三个目标。目的1测试组蛋白去乙酰化是否是分化的共同机制的一部分。其他两个目标定义的特定的抑制复合物的作用，负责抑制转录抑制因子（目的2），神经元和星形胶质细胞基因（目的3）在少突胶质细胞分化。将使用培养的祖细胞在体外进行实验，并使用条件性敲除小鼠和移植研究在体内进行实验。该模型代表了发育神经生物学领域的一个概念性进展，如果正确的话，为治疗策略的发展提供了重要的见解。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形成障碍和成人脱髓鞘修复至关重要的机制，并且因为在胶质母细胞瘤（最常见和不可治疗的脑肿瘤形式）的发生中涉及多潜能胶质祖细胞的分化缺陷。

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.