SOX19b regulates the premature neuronal differentiation of neural stem cells through EZH2-mediated histone methylation in neural tube development of zebrafish
SOX19b regulates the premature neuronal differentiation of neural stem cells through EZH2-mediated histone methylation in neural tube development of zebrafish
复制标题
SOX19b通过EZH2介导的组蛋白甲基化调节斑马鱼神经管发育中神经干细胞的过早神经元分化
DOI：
10.1186/s13287-019-1495-3
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发表时间：
2019-12-16
影响因子：
7.5
通讯作者：
Hao, Aijun
中科院分区：
文献类型：
--
作者：
Li, Xian;Zhou, Wenjuan;Hao, Aijun
目的神经管缺陷（NTD）是临床上最严重、最常见的出生缺陷。 SRY 相关的 HMG box B1 (SoxB1) 基因家族与早期胚胎发生的不同过程有关。 Sox19b 是 SoxB1 家族中的一个母系表达基因，存在于假定的中枢神经系统 (CNS) 区域，但其在神经管发育过程中胚胎神经干细胞 (NSC) 中的作用和机制尚未被探索。考虑到Sox19b是硬骨鱼所特有的，我们打算研究Sox19b在斑马鱼胚胎神经管发育中的作用和机制。材料与方法采用吗啡啉（MO）反义寡核苷酸构建Sox19b功能丧失斑马鱼模型。通过原位杂交和免疫标记分析相关基因的表型和表达。通过蛋白质印迹和染色质免疫沉淀检测表观遗传修饰。结果在本研究中，我们发现在Sox19b基因的表达受到抑制后，斑马鱼胚胎表现出前脑表型减少甚至缺失。此外，我们首次发现Sox19b的敲低会降低NSC的增殖；增加 Ngn1、Ascl1、HuC、Islet1 和细胞周期蛋白依赖性激酶 (CDK) 抑制剂的转录水平；并导致 NSC 过早分化。最后，我们发现Sox19b的敲低降低了EZH2/H3K27me3的水平，并降低了Ngn1和scl1a启动子处的H3K27me3的水平。结论综上所述，我们的数据表明Sox19b通过EZH2介导的神经管发育中的组蛋白甲基化在早期NSC增殖和分化中发挥重要作用。该研究确立了转录因子Sox19b和表观遗传因子EZH2调控网络在NSC发育中的作用，为神经管缺陷的临床治疗提供新的线索和理论指导。
ObjectiveNeural tube defects (NTDs) are the most serious and common birth defects in the clinic. The SRY-related HMG box B1 (SoxB1) gene family has been implicated in different processes of early embryogenesis. Sox19b is a maternally expressed gene in the SoxB1 family that is found in the region of the presumptive central nervous system (CNS), but its role and mechanism in embryonic neural stem cells (NSCs) during neural tube development have not yet been explored. Considering that Sox19b is specific to bony fish, we intended to investigate the role and mechanism of Sox19b in neural tube development in zebrafish embryos.Material and methodsMorpholino (MO) antisense oligonucleotides were used to construct a Sox19b loss-of-function zebrafish model. The phenotype and the expression of related genes were analysed by in situ hybridization and immunolabelling. Epigenetic modifications were detected by western blot and chromatin immunoprecipitation.ResultsIn this study, we found that zebrafish embryos exhibited a reduced or even deleted forebrain phenotype after the expression of theSox19bgene was inhibited. Moreover, we found for the first time that knockdown of Sox19b reduced the proliferation of NSCs; increased the transcription levels ofNgn1,Ascl1,HuC,Islet1, and cyclin-dependent kinase (CDK) inhibitors; and led to premature differentiation of NSCs. Finally, we found that knockdown of Sox19b decreased the levels of EZH2/H3K27me3 and decreased the level of H3K27me3 at the promoters ofNgn1andascl1a.ConclusionTogether, our data demonstrate that Sox19b plays an essential role in early NSC proliferation and differentiation through EZH2-mediated histone methylation in neural tube development. This study established the role of transcription factor Sox19b and epigenetic factor EZH2 regulatory network on NSC development, which provides new clues and theoretical guidance for the clinical treatment of neural tube defects.