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Defining the Roles of Polycomb Repressive Complex 2 (PRC2) Subcomplexes in H3 K27M Gliomas

定义 Polycomb 抑制复合物 2 (PRC2) 子复合物在 H3 K27M 胶质瘤中的作用

基本信息

批准号：
10389924
负责人：
Tyler J Reich
金额：
$ 4.11万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10389924
关键词：
Ablation Achievement Address Affinity Applications Grants Binding Biochemical Biochemistry Biological Assay Biology Brain Neoplasms CRISPR/Cas technology Cancer Biology Cell Maintenance Cell Proliferation Cells Child Childhood Childhood Brain Neoplasm Childhood Malignant Brain Tumor Chromatin Chromatin Structure Clinical Clinical Trials Collaborations Complex CpG Islands DNA Data Development Diffuse Diffuse intrinsic pontine glioma Disease Ensure Environment Event Fatal Outcome Foundations Future Gene Expression Gene Silencing Genes Genome Genomics Glioma Gliomagenesis Higher Order Chromatin Structure Histone H3 Histones Human In Vitro Kinetics Life Lysine Malignant Neoplasms Measures Mediating Mentors Methionine Methylation Methyltransferase Modeling Molecular Multienzyme Complexes Mutate Mutation Outcome Pathogenesis Patients Physicians Polycomb Post-Translational Protein Processing Predisposition Prognosis Proteomics Recurrence Regulation Reporting Research Research Personnel Residual state Resistance Resources Role Scientist Series Site Testing Therapeutic Tissues Training Tumor Suppressor Genes Tumor Suppressor Proteins Universities Variant Wisconsin Work anti-cancer base career cell growth cell type defined contribution design experimental study genome-wide glioma cell line human disease improved inhibitor innovation insight loss of function mutation mortality mouse model novel therapeutics oncohistone preclinical efficacy prevent promoter recruit therapeutic development therapeutic target tumor tumorigenesis virtual

项目摘要

PROJECT ABSTRACT/SUMMARY Cell type-specific gene expression, the basis for complex multicellular life, is achieved through packaging a common, invariant genome into higher-order chromatin structures with myriad levels of regulation. Covalent post- translational modifications (PTMs) at specific histone residues are major points of regulation that are dynamically modified throughout development to ensure proper tissue lineage specification, cell fate transitions, and maintenance of cell identity. Mutations in histone modifiers, as well as the histone substrates themselves, underlie a variety of human diseases including cancer. Recurrent lysine-to-methionine mutations at residue 27 of histone H3 (H3 K27M) are found in >80% of diffuse intrinsic pontine gliomas (DIPG), a high-grade pediatric brain cancer with dismal prognosis. The H3 K27M oncohistone drives gliomagenesis in part through its inhibition of polycomb repressive complex 2 (PRC2), the methyltransferase complex responsible for methylating H3K27, resulting in genome-wide depletion of the repressive mark H3K27me3. This proposal endeavors to address a long-observed yet poorly characterized aspect of H3K27M-driven PRC2 dysregulation: residual PRC2 activity at focal sites of H3K27me3. Leveraging biochemical, genomic, and cell- based approaches, the experiments described in this study seek to define the PRC2 subunits necessary for targeting to, and catalytic activity at, sites of PRC2 recruitment in DIPG cells. These results stand to significantly deepen our understanding of H3K27M-dysregulated chromatin and may reveal exploitable vulnerabilities for H3 K27M diffuse gliomas. The training plan outlined in this proposal will be performed at the University of Wisconsin-Madison within an excellent institutional research environment boasting cutting-edge resources, facilities, and dynamic opportunities for collaboration. Execution of this training plan, under the guidance of expert mentors and collaborators in fields of cancer biology, chromatin biochemistry, proteomics, and genomics, will provide an invaluable foundation meant to launch a successful career as a physician-scientist cancer researcher.

项目摘要/总结