Epigenetic Induction of Gliomagenesis in Neural Progenitor Cells

神经祖细胞胶质瘤发生的表观遗传诱导

基本信息

批准号：
10427712
负责人：
Gilbert J Rahme
金额：
$ 2.76万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2022-07-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10427712
关键词：
Address Affect Architecture Automobile Driving Award Azacitidine Binding Binding Proteins Binding Sites Biological Assay Brain Neoplasms CCCTC-binding factor Cancer Patient Cells Chromatin Loop Clinical Treatment CpG Island Methylator Phenotype DNA Methylation Data Development Diffuse Dioxygenases Distal Educational workshop Enhancers Environment Enzymes Epigenetic Process Equipment Event Family Functional disorder Gene Expression General Hospitals Genes Genetic Genome Glioma Gliomagenesis Goals Growth Histones Human In Vitro Institutes Isocitrate Dehydrogenase Laboratories Lead Left Lesion Lysine Massachusetts Measures Metabolic Methylation Modeling Molecular Mus Mutation Neighborhoods Oncogene Activation Oncogenes Oncogenic PDGFRA gene Patients Phenocopy Platelet-Derived Growth Factor Positioning Attribute Preclinical Testing Primary Brain Neoplasms Process Recurrence Research Role Sampling Series Shapes Signal Transduction Site Synteny Testing The Cancer Genome Atlas Training Tumor Suppressor Genes Up-Regulation Work anticancer research career cell type chromosome conformation capture demethylation epigenome editing epigenomics experimental study gain of function mutation in vivo medical schools molecular subtypes mortality mouse model multimodality mutant nerve stem cell novel promoter recruit stem cells student mentoring targeted treatment therapeutic evaluation tool tumor tumor initiation tumorigenesis

项目摘要

Project Summary Gliomas are incurable brain tumors that can be classified into distinct molecular subtypes. One glioma subtype is characterized by isocitrate dehydrogenase 1 (IDH1) gain-of-function mutations and a CpG hypermethylator profile (G-CIMP) directly caused by mutant IDH1 function. CpG methylation in a gene or promoter suppresses gene expression, hence mutant IDH1 was thought to exert its oncogenic role by silencing tumor suppressor genes. The Bernstein laboratory introduced new data that added CCCTC-binding factor (CTCF) binding sites (insulators) to the list of methylated sites in IDH mutant glioma. CTCF partitions the genome into topologically associated domains (TADs): insulated neighborhoods that allow gene-enhancer interactions inside the same TAD while restricting outside interactions. Insulator methylation disrupts TADs and allows aberrant gene- enhancer interactions to take place, driving gene expression. A recurrent insulator loss was identified in the PDGFRA oncogene locus in IDH mutant glioma, allowing for a distal enhancer to upregulate PDGFRA, driving proliferation in established glioma. It is not known whether this epigenetic mechanism can transform neural progenitor cells (NPCs): the likely glioma cell of origin. Hypothesis: Disruption of the PDGFRA insulator in NPCs is sufficient to drive hyper-proliferation and gliomagenesis. Aim 1: Determine the mechanistic effects of insulator dysfunction on PDGFRA expression in NPCs. Aim 2: Assess the consequence of insulator dysfunction on NPCs in vivo. The proposed studies will explore novel mechanisms by which glioma develops from NPCs and would be the first demonstration of an epigenetic mechanism of tumor initiation. Further, the proposed studies can suggest that treatment with hypomethylating agents (5-azacytidine) may be beneficial for mutant IDH1 glioma. Additionally, the proposed studies will establish a faithful mouse model of glioma allowing for preclinical testing of therapeutics in vivo. Mutations in IDH1, similar to those observed in glioma, can be observed in other tumors suggesting that the findings from the study can be applicable to other tumor types. Training plan and environment: The proposed research will take place in the Bernstein lab at Massachusetts General Hospital (MGH) that has spearheaded major advances in epigenomics research. All the necessary equipment is available either in the Bernstein lab or at research cores located in MGH. With affiliations at Harvard Medical School, the Broad Institute, and MGH, I will have ample opportunities to attend seminars and workshops that will help me shape my career as I progress towards an independent research position. As part of my training plan, I will also mentor students in the lab, present my research both locally and nationally, and apply to transition awards allowing me to pursue an independent career in cancer research.

项目摘要神经胶质瘤是无法治愈的脑肿瘤，可以分类为不同的分子亚型。一种胶质瘤亚型具有异位酸脱氢酶1（IDH1）功能获得突变和CPG高甲基甲的特征直接由突变IDH1函数引起的轮廓（G-CIMP）。基因或启动子中的CpG甲基化抑制基因表达，因此认为突变的IDH1通过使肿瘤抑制剂沉默发挥其致癌作用基因。伯恩斯坦实验室引入了新数据，以增加CCCTC结合因子（CTCF）结合位点（绝缘子）到IDH突变胶质瘤中的甲基化位点列表。 CTCF将基因组划分为拓扑相关域（TADS）：允许基因增强剂相互作用的绝缘邻域在限制外部互动的同时。绝缘甲基化会破坏tads并允许异常基因增强子相互作用发生，驱动基因表达。在 IDH突变神经胶质瘤中的PDGFRA癌基因基因座，允许远端增强子上调PDGFRA，驱动已建立神经胶质瘤的增殖。尚不清楚这种表观遗传机制是否可以改变神经祖细胞（NPC）：可能起源的神经胶质瘤细胞。假设：NPC中PDGFRA绝缘子的破坏足以驱动过度散热和神经胶质作用。 AIM 1：确定绝缘体功能障碍对NPC中PDGFRA表达的机械作用。目标2：评估体内NPC的绝缘体功能障碍的结果。拟议的研究将探索神经胶质瘤从NPC中发展的新机制，将是首先证明了肿瘤起始的表观遗传机制。此外，拟议的研究可以暗示用甲基化剂（5-氮杂丁胺）治疗可能对突变体IDH1神经胶质瘤有益。此外，拟议的研究将建立忠实的胶质瘤小鼠模型，以进行临床前测试体内治疗剂。在其他肿瘤中可以观察到IDH1中的突变，类似于神经胶质瘤中的突变表明该研究的发现可能适用于其他肿瘤类型。培训计划和环境：拟议的研究将在马萨诸塞州的伯恩斯坦实验室举行综合医院（MGH）率先在表观基因组学研究方面取得了重大进展。所有必要设备可以在伯恩斯坦实验室或MGH的研究核心上找到。有从属关系哈佛医学院，布罗德学院和MGH，我将有足够的机会参加研讨会和随着我朝着独立的研究职位迈进，可以帮助我塑造职业的讲习班。作为一部分在我的培训计划中，我还将在实验室中指导学生，在本地和全国范围内介绍我的研究，以及适用于过渡奖，使我能够从事癌症研究的独立职业。