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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：
10658655
负责人：
Stephen C Mack
金额：
$ 57.61万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
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 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658655
关键词：
Acetylation 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 Viral 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 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.

抽象的多梳抑制复合物 2 (PRC2) 在脑癌中反复遭到破坏；需要一个复杂的沉积抑制性组蛋白修饰，H3K27 三甲基化 (H3K27me3)。 PRC2的维护功能对于基因和重复元件的抑制很重要，可以防止异常转录。 PRC2 对于胚胎细胞的正常维持、神经干细胞分化和大脑整体发育。 PRC2 功能障碍和异常 H3K27me3 水平如何影响大脑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具有频繁的组蛋白 H3 赖氨酸 27 到蛋氨酸突变（表示为 H3K27M）的级别神经胶质瘤 (HGG)。 H3K27M 的表达会损害 PRC2 功能并导致 H3K27me3 整体缺失；的一个决定性特征这些脑肿瘤。使用删除了 H3K27M 的同基因神经胶质瘤模型，我们发现 H3K27M 导致活性转录标记 H3K27 乙酰化 (H3K27ac) 整体增加（Krug 等人，癌症细胞，2019）。令人惊讶的是，全局 H3K27ac 对基因转录的影响极小。相反，我们发现了一个 H3K27ac 相关重复 DNA 元件（即 H 型人类）转录的新机制内源性逆转录病毒（HERV）序列。我们假设：1）HERV 激活在以下方面发挥功能性作用： H3K27M 驱动的神经胶质瘤的生物学特性，以及 2) HERV 表达的扩增代表了一种新型抗癌药物针对 H3K27me3 整体缺失的肿瘤的策略。为了检验这一假设，我们提出了三个具体目标目的：1) 破译 H3K27M 驱动的神经胶质瘤中 HERV 转录激活的机制，2) 确定 HERV 表达对 H3K27M-神经胶质瘤细胞身份和肿瘤形成的影响，以及 3) 描绘 H3K27M-神经胶质瘤中 HERV 检测和反应的机制。总的来说，这些实验将揭示深入了解 HERV 表达在高级神经胶质瘤和细胞脆弱性中的作用 H3K27M 突变。