Schwann cells are the nerve ensheathing cells of the peripheral nervous system. Absence, loss and malfunction of Schwann cells or their myelin sheaths lead to peripheral neuropathies such as Charcot-Marie-Tooth disease in humans. During Schwann cell development and myelination chromatin is dramatically modified. However, impact and functional relevance of these modifications are poorly understood. Here, we analyzed histone H2B monoubiquitination as one such chromatin modification by conditionally deleting the Rnf40 subunit of the responsible E3 ligase in mice. Rnf40-deficient Schwann cells were arrested immediately before myelination or generated abnormally thin, unstable myelin, resulting in a peripheral neuropathy characterized by hypomyelination and progressive axonal degeneration. By combining sequencing techniques with functional studies we show that H2B monoubiquitination does not influence global gene expression patterns, but instead ensures selective high expression of myelin and lipid biosynthesis genes and proper repression of immaturity genes. This requires the specific recruitment of the Rnf40-containing E3 ligase by Egr2, the central transcriptional regulator of peripheral myelination, to its target genes. Our study identifies histone ubiquitination as essential for Schwann cell myelination and unravels new disease-relevant links between chromatin modifications and transcription factors in the underlying regulatory network.

中文翻译：

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Egr2引导的组蛋白H2B单泛素化对于周围神经系统的髓鞘形成是必需的。

雪旺氏细胞是周围神经系统的神经鞘细胞。雪旺氏细胞或其髓鞘的缺乏，缺失和功能障碍会导致周围神经病变，例如人类的夏科-玛丽-牙齿疾病。在雪旺氏细胞发育和髓鞘形成过程中，染色质被显着修饰。但是，这些修改的影响和功能相关性知之甚少。在这里，我们通过有条件地删除小鼠中负责任的E3连接酶的Rnf40亚基，将组蛋白H2B单泛素化分析为一种此类染色质修饰。缺乏Rnf40的Schwann细胞在髓鞘形成之前即被捕集，或产生异常稀薄，不稳定的髓磷脂，导致周围神经病变，其特征在于髓鞘形成不足和进行性轴突变性。通过将测序技术与功能性研究相结合，我们发现H2B单泛素化不会影响整体基因表达模式，而是确保了髓磷脂和脂质生物合成基因的选择性高表达以及不成熟基因的适当抑制。这需要通过外围髓鞘化的中央转录调节子Egr2将含有Rnf40的E3连接酶特异性募集到其靶基因。我们的研究确定了组蛋白泛素化对于雪旺氏细胞的髓鞘化至关重要，并揭示了染色质修饰与基础调控网络中转录因子之间与疾病相关的新联系。而是要确保髓磷脂和脂质生物合成基因的选择性高表达，并适当抑制不成熟基因。这需要通过外围髓鞘化的中央转录调节子Egr2将含有Rnf40的E3连接酶特异性募集到其靶基因。我们的研究确定了组蛋白泛素化对于雪旺氏细胞的髓鞘化至关重要，并揭示了染色质修饰与基础调控网络中转录因子之间与疾病相关的新联系。而是要确保髓磷脂和脂质生物合成基因的选择性高表达，并适当抑制不成熟基因。这需要通过外围髓鞘化的中央转录调节子Egr2将含有Rnf40的E3连接酶特异性募集到其靶基因。我们的研究确定了组蛋白泛素化对于雪旺氏细胞的髓鞘化至关重要，并揭示了染色质修饰与基础调控网络中转录因子之间与疾病相关的新联系。