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: 10573208
• 负责人: Gilbert J Rahme
• 金额: $ 16.74万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10573208
• 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; 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.

项目摘要 弥漫性神经胶质瘤是可治疗的脑肿瘤拼命攻击性疗法1-4。了解该机制 启动神经胶质瘤是改善疗法的关键一步。大多数弥漫性神经胶质瘤由 异位酸脱氢酶1（IDH1）中的错义突变，导致全基因组DNA高甲基化，A IDH1MUT神经胶质瘤的特征4-7。 DNA高甲基化可以通过沉默肿瘤促进神经胶质作用 抑制器基因8.替代性，DNA高甲基化也可能通过激活原始 - 通过CTCF绝缘子位点的破坏9-13。 CTCF绝缘子位点定义了三维 通过决定拓扑相关的结构域（TADS）14,15的边界来形成基因组的形状。增强剂 并且启动子在同一TAD中时可以相互作用，但在不同的TAD中却不能相互作用14。IDH1MUTGLIOMAS是 以CPG高度甲基化的特征在CTCF位点周围有效导致绝缘体破坏和TAD 重组，允许激活血小板来源的生长因子受体α（PDGFRA）原始 癌基因16。重要的是，TAD中断的影响严重取决于受影响基因座的增强子， 强烈的细胞型特异性12,14,17-19。我提供了初步证据表明下游绝缘体 PDGFRA在IDH1MUT神经胶质瘤中被破坏，允许与强烈增强子的异常相互作用 相邻的TAD，驱动PDGFRA表达。该神经胶质瘤增强剂在少突胶质细胞 - 促进剂中也有效 细胞（OPC），神经胶质瘤的候选细胞20-23。我还提供了证据表明 CDKN2A启动子在IDH1MUT神经胶质瘤中沉默了该肿瘤抑制剂。这些强烈的甲基化元素 可以通过DNA甲基转移酶1（DNMT1）维持整个细胞分裂，该甲基化甲基化 通过细胞复制的模式24–26。该提案的目标是（1）与胶质瘤相关的表观遗传学模型 OPC中PDGFRA和CDKN2A基因座的病变，（2）测试PDGFRA绝缘子和 CDKN2A足以从体内启动OPC的神经胶质作用，（3）测试是否表观遗传病变。 PDGFRA绝缘子和CDKN2A启动子在神经胶质瘤中被有丝分裂传播为肿瘤驱动因素。这些 研究将发现有丝分裂性的表观遗传病变足以启动弥漫性神经胶质瘤。 伯恩斯坦博士是表观遗传学领域的国际尊敬的领导者，是一位出色的心理 成功的学员。拟议的研究将在MGH，研究与医学研究所MGH进行， 一个充满活力的合作社区，包括广泛研究所和其他当地学院。研究咨询 世界一流科学家委员会将提供指导：Drs。 Suzanne Baker，MarioSuvà和Miguel Rivera。 研究的关键方面将通过与DRS的合作完成。 Chao Cheng和MarioSuvà。 K99/R00奖将为我提供在职业生涯中取得成功的最佳机会，并且将是无价的 成功过渡到独立性，使我能够启动雄心勃勃的研究计划。