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

破译异常内源性逆转录病毒表达在肿瘤组蛋白驱动的神经胶质瘤中的作用

基本信息

批准号：
9945835
负责人：
Stephen C Mack
金额：
$ 39.85万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2021-08-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9945835
关键词：
Acetylation Antiviral Agents Antiviral Response Binding Biology Brain Brain Neoplasms Cell Maintenance Cell Proliferation Cell model Cells Complex DNA DNA Methylation Deposition Detection Development Double-Stranded RNA Electroporation Elements Enzyme Activation Evolution Family member Functional disorder Genetic Transcription Glioma H3 K27M mutation Histone Acetylation Histone H3 Histones Human Human Genome Impairment Interferon Type I Knock-out Lysine Maintenance Malignant Neoplasms Malignant neoplasm of brain Methionine Methylation Mitochondria Modeling Mutate Mutation Pathway interactions Patients Pattern Play Polycomb Reader Recurrence Regulation Regulatory Pathway Repetitive Sequence Role Signal Pathway Signal Transduction Testing Therapeutic Transcriptional Activation Translational Repression Virus Diseases anti-cancer base blastomere structure cancer cell embryonic stem cell epigenetic silencing experimental study gene repression genetic approach helicase histone modification in utero inhibitor/antagonist insight neoplastic cell nerve stem cell neural growth novel novel therapeutic intervention oncohistone overexpression response self-renewal stem cell differentiation transcription factor tumor tumorigenesis

项目摘要

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.

抽象的 Polycomb抑制性复合物2（PRC2）在脑癌中反复破坏。一个需要的复杂沉积抑制性组蛋白修饰，H3K27三甲基化（H3K27me3）。维护PRC2 功能对于抑制基因和重复元素很重要，为防御异常提供了安全保护转录。 PRC2对于适当的胚胎细胞维持，神经干细胞分化和整体大脑发育。 PRC2功能障碍和异常H3K27ME3水平如何促进大脑肿瘤发生尚不清楚。作为脑肿瘤中PRC2功能障碍的模型，我们的实验室研究中线高具有频繁的组蛋白H3赖氨酸27至蛋氨酸突变（表示为H3K27M）的级胶质瘤（HGG）。 H3K27M的表达会损害PRC2功能，并导致H3K27me3的全局损失；一个定义特征的特征这些脑肿瘤。使用删除H3K27M的等源性神经胶质瘤模型，我们发现H3K27M 导致主动转录标记H3K27乙酰化（H3K27AC）的全球增加（Krug等，癌症 Cell，2019）。令人惊讶的是，全局H3K27AC对基因转录的影响很小。相反，我们发现了一个 H3K27AC相关的重复DNA元素的新机制，即Human型Human 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和2）HERV表达的扩增代表了一种新型的抗癌药针对全球损失H3K27ME3的肿瘤的战略。为了检验这一假设，我们提出了三个特定目标 TO：1）破译H3K27M驱动神经胶质瘤中HERV转录激活的机制，2）确定 HERV表达对H3K27M-glioma细胞同一性和肿瘤形成的影响，3）描绘 H3K27M-glioma中HERV检测和反应的机制。这些实验会揭示对HERV表达在高级神经胶质瘤和细胞脆弱性中的作用的机理洞察力 H3K27M突变。