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

摘要 多梳抑制复合物2（PRC 2）在脑癌中被反复破坏; 沉积抑制性组蛋白修饰，H3 K27三甲基化（H3 K27 me 3）。PRC 2的维护 功能对于基因和重复元件的抑制是重要的，提供了一个防止异常表达的安全屏障。 转录。PRC 2对于适当的胚胎细胞维持、神经干细胞分化和神经干细胞分化是必需的。 大脑的全面发展。PRC 2功能障碍和异常的H3 K27 me 3水平如何有助于大脑 肿瘤发生尚不清楚。作为脑肿瘤中PRC 2功能障碍的模型，我们的实验室研究了中线高 高级别神经胶质瘤（HGG）具有频繁的组蛋白H3赖氨酸27至甲硫氨酸突变（表示为H3 K27 M）。 H3 K27 M的表达损害PRC 2功能并导致H3 K27 me 3的整体缺失; 这些脑瘤使用H3 K27 M缺失的同基因胶质瘤模型，我们发现H3 K27 M 导致活性转录标记H3 K27乙酰化（H3 K27 ac）的整体增加（Krug等，癌 Cell，2019）。令人惊讶的是，全局H3 K27 ac对基因转录的影响最小。相反，我们发现了 H3 K27 ac与重复DNA元件转录相关的新机制，即H型人 内源性逆转录病毒（HERV）序列。我们假设：1）HERV激活在以下方面发挥功能性作用： H3 K27 M驱动的神经胶质瘤的生物学，和2）HERV表达的扩增代表了一种新的抗癌药物 针对具有H3 K27 me 3的整体缺失的肿瘤的策略。为了验证这一假设，我们提出了三个具体目标 目的：1）破译H3 K27 M驱动的胶质瘤中HERV转录激活的机制，2）确定HERV基因在胶质瘤中的表达。 HERV表达对H3 K27 M-胶质瘤细胞特性和肿瘤形成的影响，以及3）描述HERV表达对H3 K27 M-胶质瘤细胞特性和肿瘤形成的影响。 HERV检测和H3 K27 M-胶质瘤反应的机制。这些实验将揭示 对HERV表达在高级别胶质瘤和细胞脆弱性中的作用的机制性认识， H3 K27 M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.