Understanding the regulation of PRC2 activity by EZHIP and the K27M oncohistone in pediatric gliomas

项目摘要 组蛋白和其他染色质相关蛋白的翻译后调节是一种主要手段， 基因表达在正常和恶性发展过程中受到调节。多梳族蛋白是必不可少的 在人类癌症中经常发生改变。Polycomb抑制复合体2 （PRC2）在与PRC1和H3K27me3的协作的基于染色质的串扰中起作用，以启动和维持 基因沉默我们已经发现，在小儿胶质瘤中，两种抑制PRC2对H3K27me3的催化作用的药物可以抑制PRC2对H3K27me3的催化作用。 疑似肿瘤驱动因子：组蛋白H3 K27 M和EZHIP。通过K27M和EZHIP抑制PRC2活性可导致 异常基因表达、细胞分化和细胞增殖。尽管大幅度减少， 由于EZHIP或K27M引起的H3K27甲基化水平，我们的工作揭示了CpG岛上残留的H3K27me3 已知和疑似肿瘤抑制基因的启动子附近。此外，有证据表明， 残留的PRC2活性在支持肿瘤发生中起关键作用。该提案旨在利用和 扩展我们的初步研究结果，以确定K27 M和EZHIP错误调节PRC2的机制， 通过采用多学科方法促进肿瘤发生，该方法整合了生物化学，遗传学和 基因组学方法具体而言，我们将（1）确定异常PRC2活性在促进K27 M和K27 M表达中的作用。 （2）确定PRC2靶向胶质瘤中CpG岛的机制，和（3） 明确EZHIP抑制PRC2的机制。预期的结果将帮助我们制定新的理论， 为致癌组蛋白的发病机制提供了重要的机制基础。知识产生于 本研究的过程将激发未来治疗小儿神经胶质瘤的治疗努力。

PROJECT SUMMARY Post-translational regulation of histones and other chromatin-associated proteins is a major means by which gene expression is modulated during normal and malignant development. Polycomb group proteins are essential for proper development and are frequently altered in human cancers. The Polycomb Repressive Complex 2 (PRC2) functions in a collaborative chromatin-based crosstalk with PRC1 and H3K27me3 to initiate and maintain gene silencing. We have found that PRC2 catalysis of H3K27me3 is inhibited in pediatric gliomas by two suspected tumor drivers: histone H3 K27M and EZHIP. Inhibition of PRC2 activity by K27M and EZHIP can result in aberrant gene expression, cellular differentiation, and cell proliferation. Despite a substantial reduction in H3K27 methylation levels caused by EZHIP or K27M, our work has revealed residual H3K27me3 at CpG islands near promoters of known and suspected tumor suppressor genes. Furthermore, evidence suggests that this residual PRC2 activity plays a critical role in supporting tumorigenesis. This proposal seeks to leverage and extend our preliminary findings to define the mechanisms by which K27M and EZHIP misregulate PRC2 to promote tumorigenesis by employing a multi-disciplinary approach that integrates biochemical, genetic, and genomic methods. Specifically, we will (1) define the role of aberrant PRC2 activity in promoting K27M and EZHIP-containing tumors, (2) determine the mechanism of targeting PRC2 to CpG islands in gliomas, and (3) define the mechanism of PRC2 inhibition by EZHIP. Expected results will help us formulate novel theories and provide crucial mechanistic basis underlying the pathogenesis by oncohistones. The knowledge generated in the course of this study will motivate future therapeutic efforts for treating pediatric gliomas.