染色质重塑蛋白LSH通过DNA甲基化可塑性调控肿瘤细胞能量代谢的研究

DNA甲基化是染色质修饰的重要内容，有可能通过可塑性精细调控代谢重编程相关基因，调节肿瘤细胞能量代谢。申请者前期发现染色质重塑蛋白LSH通过染色质修饰介导Stalled Pol II可塑性调控, 且预实验发现LSH与G9a和WDR76相互作用，有可能分别介导靶基因的DNA甲基化即(5mC)和去甲基化（5hmC）。然而，LSH与代谢重编程之间的联系仍有待阐明。本项目将探讨LSH通过染色质修饰调节细胞能量代谢的机制，阐明LSH与WDR76及G9a相互作用并募集于靶基因TSSs区域，影响DNA甲基化可塑性修饰，发挥精确整合转录调控的作用，从而影响与细胞能量代谢相关的基因谱(如FH和EGLNs等)，促进肿瘤细胞能量代谢和EMT的进程，最终导致肿瘤细胞干细胞重编程。本项目将从全新角度探讨LSH影响染色质修饰可塑性的作用，揭示肿瘤细胞能量代谢的新机制。

As important contents of chromatin remodeling, DNA methylation plays an important role in precise regulation of metabolic reprogramming associated genes, and contributes to energy metabolism reprogramming of tumor cells. We previously demonstrate that chromatin-remodeling factor LSH regulated stalled RNA polymerase II via chromatin modification and we showed that LSH interacted with G9a and WDR76, indicating LSH plays a critical role in DNA methylation and demethylation respectively. However, the connection between LSH and metabolic reprogramming remains unknown. In this project, we will explore new regulation mechanism of cell energy metabolism through LSH mediated chromation remodeling, to clarify the interplay between LSH, WDR76 and G9a, which may be recruited around TSSs and affect DNA methylation resulting precise control of transcriptional regulation of cell energy metabolism related genes(FH, EGLNs etc.) to promote tumor cell progression and epithelial-mesenchymal transition. This project will investigate the role of LSH playing in chromatin remodeling from a new viewpoint, and provide new integrated insights into the interplay between tumor metabolic reprogramming and cancer stem cell reprogramming.