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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.

项目总结