Abstract：
The plant homeodomain finger protein Phf8 is a histone demethylase implicated by mutation in mice and humans in neural crest defects and neurodevelopmental disturbances. Considering its widespread expression in cell types of the central nervous system, we set out to determine the role of Phf8 in oligodendroglial cells to clarify whether oligodendroglial defects are a possible contributing factor to Phf8-dependent neurodevelopmental disorders. Using loss- and gain-of-function approaches in oligodendroglial cell lines and primary cell cultures, we show that Phf8 promotes the proliferation of rodent oligodendrocyte progenitor cells and impairs their differentiation to oligodendrocytes. Intriguingly, Phf8 has a strong positive impact on Olig2 expression by acting on several regulatory regions of the gene and changing their histone modification profile. Taking the influence of Olig2 levels on oligodendroglial proliferation and differentiation into account, Olig2 likely acts as an important downstream effector of Phf8 in these cells. In line with such an effector function, ectopic Olig2 expression in Phf8-deficient cells rescues the proliferation defect. Additionally, generation of human oligodendrocytes from induced pluripotent stem cells did not require PHF8 in a system that relies on forced expression of Olig2 during oligodendroglial induction. We conclude that Phf8 may impact nervous system development at least in part through its action in oligodendroglial cells.
摘要：
植物同源结构域指蛋白Phf8是一种组蛋白脱甲基酶，与小鼠和人类的神经c缺陷和神经发育障碍中的突变有关。考虑到它在中枢神经系统细胞类型中的广泛表达，我们着手确定Phf8在少突胶质细胞中的作用,以阐明少突胶质细胞缺陷是否是Phf8依赖性神经发育障碍的可能促成因素.在少突胶质细胞系和原代细胞培养物中使用功能丧失和获得方法，我们发现Phf8促进啮齿动物少突胶质细胞祖细胞的增殖并损害它们向少突胶质细胞的分化。有趣的是，Phf8通过作用于基因的几个调控区并改变其组蛋白修饰谱对Olig2表达具有强烈的积极影响。考虑到Olig2水平对少突胶质细胞增殖和分化的影响，Olig2可能在这些细胞中充当Phf8的重要下游效应物。符合这样的效应器功能，Phf8缺陷细胞中Olig2的异位表达挽救了增殖缺陷。此外,在依赖于少突胶质细胞诱导过程中Olig2强制表达的系统中,从诱导多能干细胞产生人少突胶质细胞不需要PHF8.我们得出的结论是，Phf8可能至少部分通过其在少突胶质细胞中的作用来影响神经系统的发育。
