Histone deacetylation in oligodendrocyte differentiation

描述(申请人提供)：少突胶质细胞是中枢神经系统的髓鞘形成细胞，对营养神经元的支持是必不可少的。以前的研究认为它们起源于同种的谱系限制的祖细胞群体，然而一些报告挑战了这一理论，并提出了不同的祖细胞群体是否可能共享共同的少突胶质细胞分化的分子机制的问题。在这个提议中，我们将检验这样的假设，即所有少突胶质前体细胞共享共同的表观遗传学机制，即抑制髓鞘基因表达的转录抑制物，神经和星形细胞基因需要组蛋白去乙酰化，并且对分化是必要的。根据我们的模型，祖细胞的一个共同特征是高水平的髓鞘基因表达抑制物，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，组蛋白去乙酰化(由HDACs介导)，使染色质转录不活跃，抑制物水平降低，有利于髓鞘基因的表达。成熟的少突胶质细胞通过招募有利于染色质紧凑的蛋白质来进一步沉默这些基因的表达。对于神经元和星形细胞基因的抑制，也提出了类似的机制。这一模型得到了大量的初步结果和我们之前的研究的支持。实验设计包括三个目标。目的1验证组蛋白去乙酰化是否是分化的共同机制之一。另外两个目标定义了特定的抑制复合体在少突胶质细胞分化过程中的作用，这些抑制复合体负责抑制转录抑制因子(目标2)，以及神经元和星形胶质细胞基因(目标3)。这些实验将在体外进行，使用培养的祖细胞，在体内进行，使用条件基因敲除小鼠和移植研究。该模型代表了发育神经生物学领域的概念进步，如果正确，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，因为它阐述了对修复婴儿髓鞘障碍和成人脱髓鞘至关重要的机制，以及因为多潜能胶质前体细胞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.