上海生科院揭示转录中介体Med23亚基在神经分化过程的作用

　　

　1月6日，国际学术期刊Development 在线发表了中国科学院上海生命科学研究院生物化学与细胞生物学研究所王纲研究组的研究成果Mediator Med23 deficiency enhances neural differentiation of murine embryonic stem cells through modulating BMP signaling。该论文报道了转录中介体Med23基因在胚胎干细胞向神经细胞分化过程中的重要作用。

　　王纲研究组的朱万渠、姚潇、梁燕同学系统地对Med23敲除胚胎干细胞进行干性及细胞分化的多种特征鉴定，通过多种研究手段发现Med23缺失不会改变胚胎干细胞的全能性及自我更新，但是会促进其向神经细胞方向分化。同时RNA干扰敲低其他亚基，例如Med1和Med15，并不会影响胚胎干细胞向神经分化。
  
    进一步分子机制研究发现，Med23通过调节BMP信号通路来影响胚胎干细胞向神经分化；具体地， Med23通过转录因子ETS1来控制Bmp4基因的启动子及增强子的功能，从而调控Bmp4的表达。在模式生物斑马鱼研究中发现，敲低Med23的表达水平也能促进早期神经发育。这项工作揭示了转录中介体Med23亚基在神经分化过程中的重要功能，阐明了胚胎干细胞分化过程中的一种内在的调控机制，为神经退行性疾病的细胞治疗提供了一种可能的方法和思路。

　　该工作得到了中科院、科技部以及国家自然科学基金的经费支持，研究过程中还获得了生化与细胞所研究员景乃禾、李劲松的大力支持与帮助。

原文摘要：

Mediator Med23 deficiency enhances neural differentiation of murine embryonic stem cells through modulating BMP signaling

Unraveling the mechanisms underlying early neural differentiation of embryonic stem cells (ESCs) is crucial to developing cell-based therapies of neurodegenerative diseases. Neural fate acquisition is proposed to be controlled by a ‘default’ mechanism, for which the molecular regulation is not well understood. In this study, we investigated the functional roles of Mediator Med23 in pluripotency and lineage commitment of murine ESCs. Unexpectedly, we found that, despite the largely unchanged pluripotency and self-renewal of ESCs, Med23 depletion rendered the cells prone to neural differentiation in different differentiation assays. Knockdown of two other Mediator subunits, Med1 and Med15, did not alter the neural differentiation of ESCs. Med15 knockdown selectively inhibited endoderm differentiation, suggesting the specificity of cell fate control by distinctive Mediator subunits. Gene profiling revealed that Med23 depletion attenuated BMP signaling in ESCs. Mechanistically, MED23 modulated Bmp4 expression by controlling the activity of ETS1, which is involved in Bmp4 promoter-enhancer communication. Interestingly, med23 knockdown in zebrafish embryos also enhanced neural development at early embryogenesis, which could be reversed by co-injection of bmp4 mRNA. Taken together, our study reveals an intrinsic, restrictive role of MED23 in early neural development, thus providing new molecular insights for neural fate determination.