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Chromatin Organization in Glioma Initiation

神经胶质瘤起始中的染色质组织

基本信息

批准号：
10545724
负责人：
Devin Michael Bready
金额：
$ 5.27万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-07 至 2024-01-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10545724
关键词：
3-Dimensional ATAC-seq ATRX gene Address Adjuvant Architecture Astrocytoma Binding Biological Assay Brain CCCTC-binding factor CRISPR interference CRISPR/Cas technology Cell Cycle Cell Survival Cell model Cells Characteristics Chromatin Clustered Regularly Interspaced Short Palindromic Repeats DNA Data Development Dioxygenases Distal Distal Enhancer Elements Engineering Enhancers Environment Enzyme Inhibition Enzymes Epigenetic Process Event Excision Family Fellowship Functional disorder Genes Genetic Genetic Enhancer Element Genetic Transcription Genome Genomics Glioblastoma Glioma Gliomagenesis Guide RNA Heterozygote Histones Human Hypermethylation Impairment Incidence Indolent Intergenic DNA Isocitrate Dehydrogenase Location Maintenance Malignant - descriptor Malignant Neoplasms Mediating Metabolism Modeling Molecular Conformation Mutation Nuclear Oncogenes Oncogenic Operative Surgical Procedures Other Genetics Pathway interactions Patients Pattern Phenotype Primary Brain Neoplasms Production Publishing Radiation Regulation Reporter Role Secondary to Specimen TP53 gene Testing Transcript Tumor Suppressor Proteins Undifferentiated Work alpha ketoglutarate cell type chemotherapeutic agent demethylation epigenome gain of function mutation gene interaction genomic locus histone demethylase inhibitor insight knock-down large scale production mutant neoplastic cell nerve stem cell neurodevelopment neuroregulation novel prevent promoter recruit restoration sex small hairpin RNA stem cell differentiation stem cell model transcription factor transcriptome transcriptome sequencing transcriptomics translocase treatment strategy tumor tumorigenesis young adult

项目摘要

Project Summary Glioma is the most common primary brain tumor and represents a disproportionate percentage of cancer fatalities in relation to its incidence. In the last decade, it has been discovered that nearly all lower grade gliomas harbor a characteristic gain of function mutation in Isocitrate dehydrogenase I (IDH1) allowing the enzyme to form a novel oncometabolite. These lower grade gliomas invariably progress to high-grade, aggressive glioblastoma. At neither the low-grade nor high-grade stage are directed therapies available and current treatment is limited to surgical resection and adjuvant radiation and alkylating chemotherapeutic agents. Recent efforts have attempted to employ inhibitors of mutant IDH1 to treat these tumors but early evidence is mixed, indicating that mutant IDH1 induces long-lasting epigenetic changes that do not dissipate upon inhibition of the oncometabolite’s production. Studying these tumors has proven difficult compared to IDH wildtype glioma as patient tumors cannot be readily grown in culture. To address this, our group generated a model of low-grade glioma in human neural stem cells (NSCs) which are strongly implicated as the cell of origin for these tumors. This model, referred to as 3- Hit NSCs, reaffirmed previous observations that the IDH1 mutant induces a block to neural precursor differentiation. Strikingly, it revealed that this block to differentiation in NSCs can be completely rescued by restoration of expression of the transcription factor (sex determining region Y)-box 2 (SOX2). Moreover, this reduction of expression and the associated differentiation phenotype occurs secondary to profound changes in 3-dimensional chromatin organization around the SOX2 genomic locus. The proposed work in this fellowship will examine how central these changes in chromatin organization are to the glioma-phenotype in NSCs and will characterize the SOX2 enhancer environment in NSCs to understand its regulation in glioma initiation. Preliminary data suggests that disruption of the SOX2 TAD by preventing binding of the genome organizer CTCF mirrors reduction in SOX2 expression seen in 3-Hit NSCs. Additionally, those regions which lose interaction with the SOX2 promoter in 3-Hit NSCs correlate with regions found to have marks of being active enhancers in other SOX2 expressing cell types. We hypothesize that CTCF eviction in 3-Hit NSCs results in a loss of SOX2 expression through a disruption of promoter interactions with previously uncharacterized enhancers in the SOX2 locus. To evaluate this hypothesis, I will employ complementary and independent approaches that address the involvement of CTCF mediated chromatin architecture dysfunction in glioma initiation, identify novel SOX2 enhancers in NSCs, examine the activity of these enhancers in glioma initiation, and dissect the activity of these enhancers in stem cell differentiation. Finally, I will validate the relevance of these enhancers in glioma by inferring their activity from single cell ATAC-sequencing of surgical low-grade glioma specimens. Through these approaches, paired with the support of the Placantonakis and Skok labs, I will characterize the role of chromatin disorganization in glioma initiation and help understand the developmental and oncogenic regulation of SOX2.

项目总结