Ep400 deficiency in Schwann cells causes persistent expression of early developmental regulators and peripheral neuropathy
Ep400 deficiency in Schwann cells causes persistent expression of early developmental regulators and peripheral neuropathy
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DOI：
10.1038/s41467-019-10287-w
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发表时间：
2019-05-29
影响因子：
16.6
通讯作者：
Wegner, Michael
中科院分区：
文献类型：
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作者：
Froeb, Franziska;Sock, Elisabeth;Wegner, Michael
雪旺氏细胞确保周围神经系统中有效的神经冲动传导。它们的发展伴随着明确的染色质变化，包括变异的组蛋白沉积和再分布。为了研究组蛋白变体对雪旺细胞发育的重要性，我们通过有条件地删除Tip 60/Ep 400复合物的中心亚基Ep 400来改变其基因组分布。Ep 400缺失导致小鼠的周围神经病变，其特征在于髓鞘形成和非髓鞘形成雪旺细胞的终末分化缺陷和免疫细胞活化。变异组蛋白H2A.Z在整个基因组中分布不同，并保留在Tfap 2a，Pax 3和其他转录调节基因的启动子上，在早期发育阶段具有瞬时功能。Tfap 2a在Ep 400缺陷型雪旺细胞中的缺失导致部分拯救，认为早期调节因子的持续表达介导了表型缺陷。我们的研究结果表明，正确的基因组分布的变体组蛋白是必不可少的许旺细胞分化，并分配的重要性，在这个过程中，含Ep 400染色质重塑。
Schwann cells ensure efficient nerve impulse conduction in the peripheral nervous system. Their development is accompanied by defined chromatin changes, including variant histone deposition and redistribution. To study the importance of variant histones for Schwann cell development, we altered their genomic distribution by conditionally deleting Ep400, the central subunit of the Tip60/Ep400 complex. Ep400 absence causes peripheral neuropathy in mice, characterized by terminal differentiation defects in myelinating and non-myelinating Schwann cells and immune cell activation. Variant histone H2A.Z is differently distributed throughout the genome and remains at promoters of Tfap2a, Pax3 and other transcriptional regulator genes with transient function at earlier developmental stages. Tfap2a deletion in Ep400-deficient Schwann cells causes a partial rescue arguing that continued expression of early regulators mediates the phenotypic defects. Our results show that proper genomic distribution of variant histones is essential for Schwann cell differentiation, and assign importance to Ep400-containing chromatin remodelers in the process.