人多能性干细胞印记基因MEG3异常表达相关机制的研究

The pluripotent stem cells can self-renew and differentiate into various cell types, have promising future in the research of disease models and cell replacement therapy. However, we have identified a conserved imprinted region of the mouse genome, the Dlk1-Dio3 region, which is correlated with the pluripotency levels of stem cells, and we can not obtain all-iPSC mice by tetraploid compensation when the Dlk1-Dio3 region is silence. Human iPSC also exists the phenomenon of epigenetic abnormalities that may affect the pluripotency levels and safety for differentiation cells, which seriously hampered the clinical application of iPSC. This project intends to establish MEG3 gene reporter system, and study the mechanisms of abnormal expression of imprinting genes in the processes of culture and reporgramming. In addition, we are going to screen the system for maintenance the normal imprinting status in culture, differentiation and reprogramming processes through MEG3 reporter system. This project will make it possible to provide the long-term monitoring indicators for pluripotent stem cell culture in vitro, and provide safe and reliable cell resources for transplantation and clinical applications.

诱导多能性干细胞（iPSC）具有自我更新和分化成各种细胞类型的能力，在疾病模型研究和细胞替代治疗上具有巨大的应用价值。但在小鼠上的研究发现，iPSC表观遗传学修饰存在异常，其Dlk-Dio印记基因簇包括MEG3在内的多个基因表达受到抑制，影响细胞的多能性和安全性，最终不能通过四倍体补偿获得all-iPSC小鼠。人iPSC同样存在表观遗传学异常的现象，可能影响多能性水平及分化细胞的安全性，严重阻碍了iPSC在临床上的应用。本项目拟通过建立MEG3基因报告系统，研究人多能性干细胞在培养及重编程过程印记基因的变化模式及异常表达发生的机制；同时，利用该印记基因报告系统，在体外培养和重编程过程筛选有利的培养体系，使多能性干细胞和分化获得的神经元维持正常的印记状态。本项目将有可能为多能性干细胞的长期培养提供监测指标，为干细胞移植和应用提供安全可靠的细胞资源。