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The role of H3K27M-induced aberrant PRC2 activity in brainstem gliomagenesis

H3K27M 诱导的异常 PRC2 活性在脑干胶质瘤发生中的作用

基本信息

批准号：
9172204
负责人：
Francisco Javier Cordero
金额：
$ 2.47万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-29 至 2017-05-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9172204
关键词：
Acceleration Address Affect Amino Acids Antibodies Automobile Driving Brain Stem Cell Cycle Cell Cycle Progression Characteristics Childhood Brain Neoplasm Childhood Brain Stem Neoplasm Childhood Glioma Chromatin Complex Cyclin-Dependent Kinase Inhibitor 2A Data Development Diffuse intrinsic pontine glioma EZH2 gene Enhancers Epigenetic Process Gene Expression Gene Silencing Gene Targeting Genes Genetic Transcription Genomics Glioma Gliomagenesis Goals Histones Human In Vitro Individual Island Lead LoxP-flanked allele Lysine Malignant Neoplasms Mediating Methionine Modeling Mus Mutate Mutation Neonatal Neuronal Differentiation Neurons Oncogenic PDGFB gene Pathway interactions Patients Phase Phosphorylation Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Play Polycomb Radiation Repression Research Residual state Resolution Retinoblastoma Protein Role Sampling Sequence Analysis Site Sorting - Cell Movement Staining method Stains Stem cells Survival Rate System TP53 gene Testing Transcript Tumor Suppressor Proteins Validation Variant Western Blotting Work chromatin immunoprecipitation epigenome gain of function mutation genome sequencing histone methyltransferase insight loss of function mutation mouse model mutant neoplastic cell nestin protein novel overexpression progenitor promoter public health relevance recombinase standard of care stem transcription factor transcriptome sequencing treatment strategy tumor tumorigenesis vector whole genome

项目摘要

DESCRIPTION (provided by applicant): Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable pediatric brain tumor that remains understudied. No progress in treatment has been made in the past 30 years, and radiation remains the standard of care. Recent whole-genome sequencing on tumor samples revealed heterozygous lysine-to-methionine mutations of histone variant H3.3 at amino acid residue 27(K27M) in 80% of patients. We and others have shown that K27M invokes a gain-of-function mutation which inhibits the histone methyltransferase EZH2. This inhibition causes an overall global loss of the H3K27me3 mark as well as a restructuring of the residual H3K27me3 landscape. Chromatin immunopreciptiation-sequencing (ChIP-seq) analysis of human tumors with or without K27M mutations revealed the Cdkn2a transcript variant p16 as a target of increased H3K27me3. Expression analysis of our murine H3.3K27M glioma model recapitulated these results and additionally revealed hoxa4, 5, and 7 among the most significantly downregulated genes. Since the tumor suppressor p16 is mutated in several cancers but rarely appears in DIPG, we hypothesize K27M mutations drive tumorgenesis in part by epigenetically silencing this locus. Alteration of the hox locus has been implicated in DIPG due to its role during brainstem development. Our results suggest K27M mutation inhibits differentiation of brainstem progenitors by repressing these genes. To investigate these hypotheses I propose to characterize the H3K27me3 landscape at the Cdkn2a and Hoxa loci in our murine H3.3K27M glioma model. Additionally, I will take advantage of our conditional Cdkn2a floxed model to determine the relationship between H3.3K27M mutant expression and the p16 tumor suppressor pathway with regard to oncogenic transformation. The goal of this project is to determine how mutant H3.3K27M drives tumorigenesis by manipulating the epigenome to repress the p16 and Hoxa genes. The repression of H3K27me3 at these sites may be enhancing cell cycle progression and maintaining a primitive progenitor-like state and targeting these genes with chemotherapeutics could lead to a more efficacious treatment.