Chromatin remodeler Ep400 ensures oligodendrocyte survival and is required for myelination in the vertebrate central nervous system
Chromatin remodeler Ep400 ensures oligodendrocyte survival and is required for myelination in the vertebrate central nervous system
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DOI：
10.1093/nar/gkz376
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发表时间：
2019-07-09
影响因子：
14.9
通讯作者：
Wegner, Michael
中科院分区：
文献类型：
--
作者：
Elsesser, Olga;Froeb, Franziska;Wegner, Michael
分化的少突胶质细胞产生髓磷脂以确保脊椎动物中枢神经系统中的快速跳跃传导。虽然少突胶质细胞分化和髓鞘形成伴随着显着的染色质重组，以前研究的染色质重塑只有有限的直接影响的过程。为了研究染色质变化对髓鞘形成的功能意义，并确定相关的重塑，我们删除了Ep 400，中央ATP水解亚基的TIP 60/EP 400复合物，在定义的时间小鼠少突胶质细胞的发展。而缺乏Ep 400的少突胶质细胞前体正常发育，终末分化和髓鞘形成显着受损。从机制上讲，Ep 400与转录因子Sox 10相互作用，结合到Myrf基因的调控区，并需要诱导髓鞘形成程序的中央转录调节因子。除了减少和异常的髓鞘形成，少突胶质细胞表现出增加的DNA损伤和细胞凋亡，使得在Ep 400缺陷小鼠的短寿命期间，其数量从未达到野生型水平。已经成熟的少突胶质细胞中的Ep 400缺失在表型上仍然不明显，认为Ep 400是髓鞘维持的关键。鉴于其在髓磷脂形成中的基本功能，调节Ep 400活性可能在该过程受损的多发性硬化症等病症中是有益的。
Differentiating oligodendrocytes generate myelin to ensure rapid saltatory conduction in the vertebrate central nervous system. Although oligodendroglial differentiation and myelination are accompanied by dramatic chromatin reorganizations, previously studied chromatin remodelers had only limited direct effects on the process. To study the functional significance of chromatin changes for myelination and identify relevant remodelers, we deleted Ep400, the central ATP-hydrolyzing subunit of the TIP60/EP400 complex, at defined times of mouse oligodendrocyte development. Whereas Ep400-deficient oligodendrocyte precursors develop normally, terminal differentiation and myelination are dramatically impaired. Mechanistically, Ep400 interacts with transcription factor Sox10, binds to regulatory regions of the Myrf gene and is required to induce this central transcriptional regulator of the myelination program. In addition to reduced and aberrant myelin formation, oligodendrocytes exhibit increased DNA damage and apoptosis so that numbers never reach wildtype levels during the short lifespan of Ep400-deficient mice. Ep400 deletion in already mature oligodendrocytes remains phenotypically inapparent arguing that Ep400 is dispensable for myelin maintenance. Given its essential function in myelin formation, modulation of Ep400 activity may be beneficial in conditions such as multiple sclerosis where this process is compromised.