Modeling and Dissecting Epigenetic Drivers of Gliomagenesis

神经胶质瘤发生的表观遗传驱动因素的建模和剖析

• 批准号: 10877343
• 负责人: Gilbert J Rahme
• 金额: $ 24.9万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10877343
• 关键词: 3-Dimensional; Advisory Committees; Affect; Automobile Driving; Award; Binding; Binding Sites; Brain Neoplasms; CCCTC-binding factor; CDKN2A gene; Cell division; Cells; Characteristics; Collaborations; Combined Modality Therapy; Communities; CpG Island Methylator Phenotype; DNA; DNA Methylation; DNA Modification Methylases; Diffuse; Elements; Enhancers; Enzymes; Epigenetic Process; Event; Functional disorder; Gene Activation; Gene Expression; Genes; Genetic; Genome; Glioma; Gliomagenesis; Heritability; Human; Hypermethylation; In Vitro; Inherited; International; Isocitrate Dehydrogenase; Lesion; Malignant - descriptor; Mediating; Medical; Mentors; Metabolic; Methylation; Missense Mutation; Mitotic; Modeling; Mus; Mutation; Platelet Activation; Platelet-Derived Growth Factor alpha Receptor; Primary Brain Neoplasms; Proliferating; Proto-Oncogenes; Recording of previous events; Research; Role; Scientist; Shapes; Site; Structure; Synteny; Testing; Tumor Suppressor Genes; Tumor Suppressor Proteins; aggressive therapy; career; cell type; epigenetic regulation; epigenome; genome-wide; improved; in vivo; in vivo Model; inhibitor; methylation pattern; mutant; novel therapeutic intervention; oligodendrocyte progenitor; programs; promoter; stem cells; tumor; tumor initiation

PROJECT SUMMARY Diffuse gliomas are incurable brain tumors despite aggressive therapies 1–4. Understanding the mechanisms that initiate gliomas is a critical step towards improving therapies. The majority of diffuse gliomas are driven by missense mutations in Isocitrate Dehydrogenase 1 (IDH1) which cause genome-wide DNA hypermethylation, a characteristic of IDH1mut gliomas 4–7. DNA hypermethylation may promote gliomagenesis by silencing tumor suppressor genes 8. Alternatively, DNA hypermethylation may also promote gliomagenesis by activating proto- oncogenes through disruption of CTCF insulator sites 9–13. CTCF insulator sites define the three-dimensional shape of the genome by dictating the boundaries of topologically associated domains (TADs) 14,15. Enhancers and promoters can interact when located in the same TAD but not across different TADs 14. IDH1mut gliomas are characterized with CpG hypermethylation around CTCF sites, effectively leading to insulator disruption and TAD reorganization, allowing for the activation of the platelet-derived growth factor receptor α (PDGFRA) proto- oncogene 16. Importantly, the effects of TAD disruption critically depend on the enhancers in the affected loci, which are strongly cell-type specific 12,14,17–19. I present preliminary evidence that an insulator downstream PDGFRA is disrupted in IDH1mut gliomas, allowing for aberrant interactions with a strong enhancer in a neighboring TAD, driving PDGFRA expression. This glioma enhancer is also active in oligodendrocyte-progenitor cells (OPCs), candidate cells-of-origin for glioma 20–23. I also present evidence that robust hypermethylation of the CDKN2A promoter silenced this tumor suppressor in IDH1mut gliomas. These strongly methylated elements can be maintained throughout cell division by DNA methyltransferase 1 (DNMT1), which maintains methylation patterns through cell replication 24–26. The objectives of this proposal are to (1) Model glioma-relevant epigenetic lesions at the PDGFRA and CDKN2A loci in OPCs, (2) Test whether disruption of the PDGFRA insulator and CDKN2A is sufficient to initiate gliomagenesis from OPCs in vivo, and (3) Test whether the epigenetic lesions at the PDGFRA insulator and CDKN2A promoter are mitotically propagated as tumor drivers in glioma. These studies will uncover whether mitotically heritable epigenetic lesions are sufficient to initiate diffuse gliomas. Dr. Bernstein is an internationally respected leader in epigenetics and an outstanding mentor with a history of successful trainees. The proposed research will be carried out at MGH, a research and medical institute, part of a vibrant collaborative community that includes the Broad Institute and other local institutes. A research advisory committee of world-class scientists will provide guidance: Drs. Suzanne Baker, Mario Suvà, and Miguel Rivera. Critical aspects of the research will be completed through collaborations with Drs. Chao Cheng and Mario Suvà. The K99/R00 award will provide me with the best opportunity to succeed in my career and will be invaluable for a successful transition to independence, allowing me to start an ambitious research program.

项目概要 尽管采取积极治疗，弥漫性神经胶质瘤仍是无法治愈的脑肿瘤 1-4。了解其中的机制 引发神经胶质瘤是改善治疗的关键一步。大多数弥漫性胶质瘤是由 异柠檬酸脱氢酶 1 (IDH1) 的错义突变会导致全基因组 DNA 高甲基化，这是一种 IDH1mut 神经胶质瘤 4-7 的特征。 DNA高甲基化可能通过沉默肿瘤来促进神经胶质瘤发生 抑制基因 8. 或者，DNA 高甲基化也可能通过激活原基因来促进神经胶质瘤发生 通过破坏 CTCF 绝缘体位点 9-13 来产生癌基因。 CTCF 绝缘体位置定义了三维 通过规定拓扑相关域 (TAD) 的边界来确定基因组的形状 14,15。增强剂 和启动子位于同一 TAD 时可以相互作用，但不能跨不同 TAD 14。IDH1mut 神经胶质瘤是 CTCF 位点周围的 CpG 高甲基化，有效导致绝缘体破坏和 TAD 重组，允许激活血小板衍生生长因子受体 α (PDGFRA) 原型 癌基因 16。重要的是，TAD 破坏的影响关键取决于受影响位点的增强子， 它们具有很强的细胞类型特异性 12,14,17–19。我提供初步证据表明下游绝缘体 PDGFRA 在 IDH1mut 神经胶质瘤中被破坏，从而与强增强子发生异常相互作用 邻近的 TAD，驱动 PDGFRA 表达。这种神经胶质瘤增强剂在少突胶质细胞祖细胞中也有活性 细胞 (OPC)，神经胶质瘤 20-23 的候选起源细胞。我还提供了证据表明， CDKN2A 启动子使 IDH1mut 神经胶质瘤中的肿瘤抑制因子沉默。这些强甲基化元素 DNA 甲基转移酶 1 (DNMT1) 可在整个细胞分裂过程中维持甲基化 细胞复制的模式 24-26。该提案的目标是 (1) 模拟神经胶质瘤相关的表观遗传 OPCs 中 PDGFRA 和 CDKN2A 位点的损伤，(2) 测试 PDGFRA 绝缘体是否受到破坏， CDKN2A 足以在体内启动 OPC 的胶质瘤生成，并且 (3) 测试表观遗传损伤是否 PDGFRA 绝缘体和 CDKN2A 启动子作为神经胶质瘤中的肿瘤驱动因子进行有丝分裂传播。这些 研究将揭示有丝分裂遗传性表观遗传损伤是否足以引发弥漫性神经胶质瘤。 伯恩斯坦博士是国际上受人尊敬的表观遗传学领军人物，也是一位具有悠久历史的杰出导师。 成功的实习生。拟议的研究将在 MGH 进行，这是一个研究和医疗机构，是 一个充满活力的合作社区，包括布罗德研究所和其他当地机构。研究咨询 世界级科学家委员会将提供指导：博士。苏珊·贝克、马里奥·苏瓦和米格尔·里维拉。 该研究的关键方面将通过与博士的合作来完成。程超和马里奥·苏瓦。 K99/R00 奖项将为我提供在职业生涯中取得成功的最佳机会，并且对于我来说是无价的 成功过渡到独立，使我能够开始一项雄心勃勃的研究计划。