Nzf2 promotes oligodendrocyte differentiation and regeneration via repressing HDAC1-mediated histone deacetylation

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2024-12-13 DOI:10.1126/sciadv.adf8405

Xiaofeng Xu, Minxi Fang, Lixia Chen, Hao Huang, Zhong-Min Dai, Junlin Yang, Mengsheng Qiu

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Abstract

Proper axonal myelination and function of the vertebrate central nervous system rely largely on the timely differentiation of oligodendrocytes (OLs), yet key regulatory factors remain enigmatic. Our study reveals neural zinc finger (Nzf2) as a crucial orchestrator that controls the timing of OL differentiation both during development and myelin repair, contrasting with its previously suggested role in direct myelin gene regulation. Nzf2 ablation delays the onset of OL differentiation, while hyperactivation stimulates OL differentiation both during development and remyelination. Using RNA-seq and ChIP-seq, we pinpoint Nkx2.2 as a critical downstream target of Nzf2. Specific binding of Nzf2 in the Nkx2.2 gene locus inhibits histone deacetylation by disrupting the HDAC1 repressor complex and reducing deacetylase activity. Furthermore, Nzf2 overrides the inhibitory Notch signaling to initiate OL differentiation. Thus, we propose that the Notch-Nzf2-Nkx2.2 axis is a vital component of OL differentiation timing mechanism, suggesting Nzf2 as a potential therapeutic target for stimulating OL differentiation and boosting myelin repair in demyelinating diseases.

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脊椎动物中枢神经系统正常的轴突髓鞘化和功能在很大程度上依赖于少突胶质细胞（OL）的及时分化，然而关键的调控因子仍然是个谜。我们的研究揭示了神经锌指（Nzf2）在发育和髓鞘修复过程中是控制少突胶质细胞分化时间的关键调控因子，这与之前提出的它在直接髓鞘基因调控中的作用形成了鲜明对比。Nzf2 消融会推迟髓鞘分化的开始，而过度激活则会刺激发育和髓鞘再形成过程中的髓鞘分化。通过RNA-seq和ChIP-seq，我们确定Nkx2.2是Nzf2的一个关键下游靶点。Nzf2在Nkx2.2基因位点的特异性结合通过破坏HDAC1抑制复合物和降低去乙酰化酶的活性来抑制组蛋白去乙酰化。此外，Nzf2还能抑制Notch信号，启动OL分化。因此，我们认为Notch-Nzf2-Nkx2.2轴是OL分化时机机制的重要组成部分，这表明Nzf2是刺激OL分化和促进脱髓鞘疾病髓鞘修复的潜在治疗靶点。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.