唾液酸化修饰通过介导蛋白质与染色质结合调控细胞命运

Cell fate regulation is one of the most important issues in stem cell and regenerative medicine. Sialylation is reported to be involved in cell fate decision during development, reprogramming and cancer progression. However, the mechanisms of sialylation regulating cell fate are poorly elucidated. Our recent preliminary data showed that the total sialylation and sialilome were significantly changed during reprogramming. Additionally, it was identified that chromatin binding proteins were sialylated and sialylation regulated protein binding to chromatin. Furthermore, somatic cell reprogramming was inhibited and the gene expression was significantly altered when sialylation changed. This prompted us to study the mechanisms of cell fate regulated by sialylation during somatic cell reprogramming. Based on our previous work, we will firstly identify sialylated proteins binding to chromatin in different cell stages during reprogramming, and then the DNA sequences bound by sialylated proteins followed by the 3D chromatin interations mediated by sialylation. Finally, combined with gene expression and cell function analysis, the molecular mechanisms underlying the role of sialylation regulating cell fate will be elucidated. It will provide new insights about the mechanisms in cell fate regulation and new evidence for regenerative medicine and disease treatment.

细胞命运调控是干细胞及再生医学领域重要的研究问题。唾液酸化修饰与个体发育、体细胞重编程、癌症发生发展过程中的细胞命运密切相关。然而，鲜有研究报道唾液酸化修饰调控细胞命运的分子机制。预实验结果显示，唾液酸化修饰蛋白组在重编程过程中发生显著变化，染色质结合蛋白具有唾液酸化修饰，并且唾液酸化修饰影响蛋白与染色质结合。唾液酸化修饰降低，抑制体细胞重编程，调控基因表达。综上，唾液酸化修饰可能通过调控蛋白与染色质结合而调控细胞命运。本项目拟在前期工作基础上，研究唾液酸化修饰调控细胞命运的分子机制：首先，在重编程不同阶段，鉴定与染色质结合的唾液酸化修饰蛋白组；其次，鉴定唾液酸化修饰蛋白结合的DNA序列；然后，分析唾液酸化修饰蛋白介导的染色质三维互作，解析唾液酸化修饰调控细胞命运的分子机制。此研究不仅有助于我们深入认识细胞命运调控的分子机制，还可能推动干细胞及再生医学的临床应用。

基于干细胞的修复与再生能力的再生医学，对解决由创伤、疾病、遗传或衰老造成的组织器官缺损、衰竭或功能障碍等人类面临的重大医学难题，具有重要作用。尽管目前干细胞已用来治疗一些疾病，但目前仅限于眼科疾病，并且仅限于少数个体治疗，且临床效有限。细胞命运调控是干细胞及再生医学领域重要的研究问题。干细胞多能性受转录因子、表观遗传因子、信号通路分子等多种因子共同调控，这些因子的功能受其翻译后修饰（Protein Translational Modifications, PTMs) 水平的影响。蛋白质翻译后修饰包括多种类型，如甲基化、乙酰化、磷酸化、泛素化、糖基化等，能在基因转录表达后调节蛋白质的结构和生理功能。唾液酸化修饰是一种性质特殊也备受关注的糖基化类型，目前已有一些研究表明，唾液酸化修饰与干细胞多能性密切相关。本研究旨在深层次解析唾液酸化修饰调控细胞命运的分子机制：鉴定重编程不同阶段细胞的与染色质结合的唾液酸化修饰蛋白组；鉴定唾液酸化修饰蛋白组在染色质上的结合位置及唾液酸化蛋白介导的染色质三维互作；解析唾液酸化修饰调控基因表达及细胞命运的分子机制。本研究结果表明，唾液酸化修饰蛋白组在重编程过程中发生显著变化，唾液酸化修饰对干细胞多能性维持至关重要；唾液酸化修饰组学显示细胞核蛋白具有唾液酸化修饰；并且，唾液酸化修饰影响蛋白与染色质结合。唾液酸化修饰降低，抑制体细胞重编程，调控基因表达。并且，本研究还鉴定了唾液酸化修饰蛋白在染色质上有高密度结合，与基因密度正相关，主要富集于基因启动子区域。然后，我们证实唾液酸化修饰蛋白介导的染色质三维互作，并证实唾液酸化修饰通过调控蛋白与染色质结合而调控细胞命运。此研究不仅有助于我们深入认识细胞命运调控的分子机制，还可能推动干细胞及再生医学的临床应用。