MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1.

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE International Journal of Oral Science Pub Date : 2023-10-18 DOI:10.1038/s41368-023-00253-0
Chen Zhang, Weilong Ye, Mengyao Zhao, Lujue Long, Dengsheng Xia, Zhipeng Fan
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Abstract

Mesenchymal stem cell (MSC)-based therapy has emerged as a promising treatment for spinal cord injury (SCI), but improving the neurogenic potential of MSCs remains a challenge. Mixed lineage leukemia 1 (MLL1), an H3K4me3 methyltransferases, plays a critical role in regulating lineage-specific gene expression and influences neurogenesis. In this study, we investigated the role and mechanism of MLL1 in the neurogenesis of stem cells from apical papilla (SCAPs). We examined the expression of neural markers, and the nerve repair and regeneration ability of SCAPs using dynamic changes in neuron-like cells, immunofluorescence staining, and a SCI model. We employed a coimmunoprecipitation (Co-IP) assay, real-time RT-PCR, microarray analysis, and chromatin immunoprecipitation (ChIP) assay to investigate the molecular mechanism. The results showed that MLL1 knock-down increased the expression of neural markers, including neurogenic differentiation factor (NeuroD), neural cell adhesion molecule (NCAM), tyrosine hydroxylase (TH), βIII-tubulin and Nestin, and promoted neuron-like cell formation in SCAPs. In vivo, a transplantation experiment showed that depletion of MLL 1 in SCAPs can restore motor function in a rat SCI model. MLL1 can combine with WD repeat domain 5 (WDR5) and WDR5 inhibit the expression of neural markers in SCAPs. MLL1 regulates Hairy and enhancer of split 1 (HES1) expression by directly binds to HES1 promoters via regulating H3K4me3 methylation by interacting with WDR5. Additionally, HES1 enhances the expression of neural markers in SCAPs. Our findings demonstrate that MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1. These results provide a potential therapeutic target for promoting the recovery of motor function in SCI patients.

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MLL1通过与WDR5相互作用和抑制HES1来抑制SCAPs的神经源性潜能。
基于间充质干细胞(MSC)的治疗已成为治疗脊髓损伤(SCI)的一种有前途的方法,但提高MSC的神经源性潜力仍然是一个挑战。混合谱系白血病1(MLL1)是一种H3K4me3甲基转移酶,在调节谱系特异性基因表达和影响神经发生方面发挥着关键作用。在本研究中,我们研究了MLL1在根尖乳头干细胞(SCAPs)神经发生中的作用和机制。我们使用神经元样细胞的动态变化、免疫荧光染色和SCI模型检测了神经标记物的表达以及SCAP的神经修复和再生能力。我们采用共免疫沉淀(Co-IP)分析、实时RT-PCR、微阵列分析和染色质免疫沉淀(ChIP)分析来研究其分子机制。结果表明,MLL1敲除增加了神经源性分化因子(NeuroD)、神经细胞粘附分子(NCAM)、酪氨酸羟化酶(TH)、βIII微管蛋白和巢蛋白等神经标志物的表达,并促进了SCAPs中神经元样细胞的形成。体内移植实验表明,SCAPs中MLL1的缺失可以恢复大鼠SCI模型的运动功能。MLL1可以与WD重复结构域5(WDR5)结合,WDR5抑制SCAP中神经标志物的表达。MLL1通过与WDR5相互作用调节H3K4me3甲基化,直接与HES1启动子结合,从而调节Hairy和分裂1增强子(HES1)的表达。此外,HES1增强了SCAP中神经标记物的表达。我们的研究结果表明,MLL1通过与WDR5相互作用和抑制HES1来抑制SCAPs的神经源性潜力。这些结果为促进SCI患者运动功能的恢复提供了一个潜在的治疗靶点。
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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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