Department of Biological Sciences, College of Arts and Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
Computational Biology Program, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
Cell Rep. 2020 Sep 15;32(11):108147. doi: 10.1016/j.celrep.2020.108147.
PRC2 creates the repressive mark histone H3 Lys27 trimethylation. Although PRC2 is involved in various biological processes, its role in glial development remains ambiguous. Here, we show that PRC2 is required for oligodendrocyte (OL) differentiation and myelination, but not for OL precursor formation. PRC2-deficient OL lineage cells differentiate into OL precursors, but they fail to trigger the molecular program for myelination, highlighting that PRC2 is essential for directing the differentiation timing of OL precursors. PRC2 null OL lineage cells aberrantly induce Notch pathway genes and acquire astrocytic features. The repression of the Notch pathway restores the myelination program and inhibits abnormal astrocytic differentiation in the PRC2-deficient OL lineage, indicating that Notch is a major target of PRC2. Altogether, our studies propose a specific action of PRC2 as a novel gatekeeper that determines the glial fate choice and the timing of OL lineage progression and myelination by impinging on the Notch pathway.
PRC2 会生成具有抑制性的组蛋白 H3K27 三甲基化标记。尽管 PRC2 参与了多种生物学过程，但它在神经胶质细胞发育中的作用仍不明确。在这里，我们发现 PRC2 对于少突胶质细胞（OL）分化和髓鞘形成是必需的，但对于 OL 前体细胞的形成则并非如此。PRC2 缺陷的 OL 谱系细胞分化为 OL 前体细胞，但它们无法触发髓鞘形成的分子程序，这表明 PRC2 对于指导 OL 前体细胞的分化时间是至关重要的。PRC2 缺失的 OL 谱系细胞异常诱导 Notch 通路基因，并获得星形胶质细胞的特征。Notch 通路的抑制恢复了髓鞘形成程序，并抑制了 PRC2 缺陷的 OL 谱系中异常的星形胶质细胞分化，表明 Notch 是 PRC2 的一个主要靶点。总的来说，我们的研究提出了 PRC2 的一个特定作用，即作为一个新的守门员，通过影响 Notch 通路来决定神经胶质细胞的命运选择以及 OL 谱系进展和髓鞘形成的时间。
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