Deciphering the Role of Aberrant Endogenous Retroviral Expression in Onco-histone Driven Glioma

摘要 多梳抑制复合体2(PRC2)在脑癌中反复中断；这是一种需要 沉积抑制性组蛋白修饰，H3K27三甲基化(H3K27me3)。PRC2的维护 功能对抑制基因和重复元件很重要，提供了一种防止异常的安全措施 抄写。PRC2对于适当的胚胎细胞维持、神经干细胞分化和 全面的大脑发育。PRC2功能障碍和H3K27me3水平异常对大脑的影响 肿瘤发生机制尚不清楚。作为脑肿瘤中PRC2功能障碍的模型，我们的实验室研究了中线高 组蛋白H3赖氨酸27到蛋氨酸突变频繁的级别胶质瘤(HGG)(表示为H3K27M)。 H3K27M的表达损害了PRC2的功能，并导致H3K27me3的全球丢失； 这些脑瘤。使用H3K27M缺失的同基因胶质瘤模型，我们发现H3K27M 导致活跃转录标志H3K27乙酰化(H3K27ac)的全球增加(Krug等人，癌症 细胞，2019年)。令人惊讶的是，全球H3K27ac对基因转录的影响微乎其微。相反，我们发现了一个 H3K27ac联合转录重复DNA元件的新机制，即H型人 内源性逆转录病毒(HERV)序列。我们假设：1)HERV激活在 H3K27M驱动的神经胶质瘤的生物学特性；2)HERV表达的扩增代表了一种新的抗癌药物 针对全球丢失H3K27me3的肿瘤的策略。为了验证这一假设，我们提出了三个具体目标 为了：1)破译H3K27M驱动的胶质瘤中HERV转录激活的机制；2)确定H3K27M驱动的胶质瘤中 HERV表达对H3K27M-胶质瘤细胞特性和肿瘤形成的影响 H3K27M-胶质瘤中HERV的检测和应答机制总的来说，这些实验将揭示 HERV表达在高级别胶质瘤和由HERV引起的细胞脆弱性中的作用机制洞察 H3K27M突变。

ABSTRACT The polycomb repressive complex 2 (PRC2) is recurrently disrupted in brain cancer; a complex required for depositing the repressive histone modification, H3K27 tri-methylation (H3K27me3). Maintenance of PRC2 function is important for repression of genes and repetitive elements, providing a safe-guard against aberrant transcription. PRC2 is essential for proper embryonic cell maintenance, neural stem cell differentiation, and overall brain development. How PRC2 dysfunction and aberrant H3K27me3 levels contributes to brain tumorigenesis is unclear. As a model of PRC2 dysfunction in brain tumors, our lab investigates midline high grade gliomas (HGG) that harbor frequent histone H3 lysine 27 to methionine mutations (denoted H3K27M). Expression of H3K27M impairs PRC2 function and results in a global loss of H3K27me3; a defining feature of these brain tumors. Using isogenic glioma models in which H3K27M is deleted, we found that the H3K27M results in a global increase in a mark of active transcription, H3K27 acetylation (H3K27ac) (Krug et al., Cancer Cell, 2019). Surprisingly, global H3K27ac has minimal effects on gene transcription. Instead, we discovered a novel mechanism of H3K27ac associated transcription of repetitive DNA elements, namely Type-H human endogenous retroviral (HERV) sequences. We hypothesize that: 1) HERV activation plays a functional role in the biology of H3K27M-driven glioma, and 2) Amplification of HERV expression represents a novel anti-cancer strategy against tumors with global loss of H3K27me3. To test this hypothesis we propose three specific aims to: 1) Decipher the mechanisms of HERV transcriptional activation in H3K27M-driven glioma, 2) Determine the impact of HERV expression on H3K27M-glioma cell identity and tumor formation, and 3) Delineate the mechanisms of HERV detection and response in H3K27M-glioma. Collectively these experiments will reveal mechanistic insight into the role of HERV expression in high-grade glioma and cellular vulnerabilities created by H3K27M mutations.