Polycomb Protein EED Regulates Neuronal Differentiation through Targeting SOX11 in Hippocampal Dentate Gyrus
Polycomb Protein EED Regulates Neuronal Differentiation through Targeting SOX11 in Hippocampal Dentate Gyrus
复制标题
Polycomb 蛋白 EED 通过靶向海马齿状回中的 SOX11 调节神经元分化
DOI：
10.1016/j.stemcr.2019.05.010
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发表时间：
2019-07-09
影响因子：
5.9
通讯作者：
Liu, Chang-Mei
中科院分区：
文献类型：
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作者：
Liu, Pei-Pei;Xu, Ya-Jie;Liu, Chang-Mei
EED（embryonic ectoderm development）是Polycomb repressive complex 2（PRC 2）的核心组分，PRC 2在胚胎干细胞的自我更新、增殖和分化过程中催化组蛋白H3赖氨酸27（H3 K27）的甲基化。然而，它在哺乳动物神经系统中的功能仍然未被探索。在这里，我们报告说，损失的EED在大脑中导致出生后的致命性，受损的神经元分化，和畸形的齿状回。Sox 11是EED的下游靶点，通过与H3 K27 me 1相互作用，过表达Sox 11可恢复EED消融的神经干/祖细胞（NSPCs）的神经元分化能力。有趣的是，Cdkn 2a的下调，EED的另一个下游靶点，其以H3 K27 me 3依赖性方式调节，逆转了EED消融的NSPCs的增殖缺陷。总之，这些发现确立了EED在海马齿状回发育中的关键作用，这可能为EED突变患者智力残疾的分子机制提供新的线索。
EED (embryonic ectoderm development) is a core component of the Polycomb repressive complex 2 (PRC2) which catalyzes the methylation of histone H3 lysine 27 (H3K27) during the process of self-renewal, proliferation, and differentiation of embryonic stem cells. However, its function in the mammalian nervous system remains unexplored. Here, we report that loss of EED in the brain leads to postnatal lethality, impaired neuronal differentiation, and malformation of the dentate gyrus. Overexpression of Sox11, a downstream target of EED through interaction with H3K27me1, restores the neuronal differentiation capacity of EED-ablated neural stem/progenitor cells (NSPCs). Interestingly, downregulation of Cdkn2a, another downstream target of EED which is regulated in an H3K27me3-dependent manner, reverses the proliferation defect of EED-ablated NSPCs. Taken together, these findings established a critical role of EED in the development of hippocampal dentate gyrus, which might shed new light on the molecular mechanism of intellectual disability in patients with EED mutations.