Role of Histone and Histone-like Mutations in the Oncogenesis of Human Cancers

组蛋白和组蛋白样突变在人类癌症发生中的作用

基本信息

批准号：
10269903
负责人：
CHARLES DAVID ALLIS
金额：
$ 146.13万
依托单位：
ROCKEFELLER 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：
2015-09-09 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10269903
关键词：
ATAC-seq Address Affect Animal Model Astrocytoma Bar Codes Biochemical Biochemical Genetics Biology Bone neoplasms Brain Neoplasms Cancer Model Cell Culture Techniques Cell Fate Control Cell Line Cell physiology Cells ChIP-seq Chemicals Chemistry Chromatin Chromatin Structure Classification Clinical Complex DNA Repair DNA methylation profiling Data Development Diagnosis Enzymes Ependymoma Epigenetic Process Frequencies Future Gene Expression Genetic Genetic Screening Genetic Transcription Genomic approach Glioma Goals Grant Histone H3 Histones Human In Vitro Investigation Lead Libraries Light Malignant Neoplasms Mediating Mesenchymal Mesenchymal Cell Neoplasm Modeling Molecular Mutation N-terminal Nature Nucleosomes Oncogenic PRC1 Protein Pathogenesis Pathogenicity Patients Phenotype Polycomb Polymers Post-Translational Protein Processing Posterior Fossa Pre-Clinical Model Process Proteins Proteomics Recurrence Role Sampling Screening procedure Somatic Mutation Structure System Tail Testing Therapeutic Trans-Activators Transgenic Organisms Work Yeasts base big gastrin biochemical tools chromatin remodeling design driver mutation epigenome epigenomics gene repression in vivo insight interdisciplinary approach member mouse model mutant novel oncohistone overexpression programs small molecule inhibitor theories therapeutic development transcriptome sequencing transcriptomics tumor tumorigenesis tumorigenic yeast genetics

项目摘要

Project Summary (Overall) The chromatin landscape impacts fundamental cellular processes including gene expression, DNA damage repair, and cell fate and differentiation, all of which are extensively dysregulated in cancer. The collective number of oncogenic mutations in chromatin regulators has led to the emerging view of driver mutations underlying cancer epigenomes. In keeping with theme, over the past several years our current collaborative program members have been critical to the discovery and characterization of ‘classical’ oncohistone mutations in the histone H3.3 N-terminal tail. These mutations globally alter chromatin by inhibiting the activity of chromatin modifying enzymes. While much progress has been made to understand these effects, important questions remain including the nature of the dysregulation of chromatin modifying enzymes by these mutations and how these mutations lead to cancer. In addition, Program members have recently identified an expanded number of cancer-associated somatic histone mutations that occur in as many as 4 % of human cancers and involve both globular and tail domains of all four core histones. These findings generate additional important questions such as if the newly observed histone mutations have functional effects on chromatin and through what mechanisms they rely on. Given that some of the most prevalent mutations are in the globular domains of histones, we hypothesize that these mutations affect nucleosome structure and/or integrity. Lastly, we and others have also identified a novel function of the EZHIP protein, which is overexpressed in posterior fossa A ependymomas, and acts as an oncohistone mimic to directly inhibit the Polycomb Repressive Complex 2 (PRC2) function. The single goal of our Program is to illuminate the molecular mechanisms underlying classical and novel “oncohistone” mutations and oncohistone mimics to advance the diagnosis and exploration of therapeutic avenues for the cancers. Specifically, we will: i) develop and employ novel patient sample-, cell culture- and animal model-based systems to recapitulate oncohistone-associated cancers and investigate the underlying pathogenic mechanisms; ii) evaluate the activity of a comprehensive set of novel cancer-associated histone mutations using a multidisciplinary approach that includes genetics (barcoded oncohistone libraries, mouse models, barcoded-cell lines), epigenetics (ChIP-seq, ATAC-seq, DNA-methylation profiling), transcriptomics (RNA-seq), and chemical biology (“designer chromatin”, small molecule inhibitors); iii) define the mechanisms by which oncohistones, and oncohistone-mimics, dysregulate the Polycomb Repressive Complexes (PRC1 and PRC2) activity to promote gliomas and bone tumors; and iv) identify which of novel histone mutations perturb chromatin states (and by what mechanisms) to subsequently cause cellular phenotype using newly developed high-throughput biochemical and yeast genetic screening tools. These studies will inform future work towards the development of therapeutic strategies designed to ameliorate the pathogenic effects of histone mutations and oncohistone mimics in cancer.

项目概要（总体）染色质景观影响基本细胞过程，包括基因表达、DNA 损伤修复、细胞命运和分化，所有这些在癌症中普遍失调。染色质调节因子中致癌突变的研究导致了驱动突变的新观点与主题一致，在过去几年中我们目前的合作项目。成员对“经典”癌组蛋白突变的发现和表征至关重要这些突变通过抑制染色质活性来全局改变染色质。虽然在理解这些效应方面已经取得了很大进展，但重要的问题仍然存在。仍然包括这些突变导致染色质修饰酶失调的性质以及如何此外，计划成员最近发现了更多的突变。与癌症相关的体细胞组蛋白突变发生在多达 4% 的人类癌症中，并且涉及所有四个核心组蛋白的球状和尾部结构域都产生了其他重要问题，例如。好像新观察到的组蛋白突变对染色质具有功能性影响以及通过什么机制鉴于一些最常见的突变发生在组蛋白的球状结构域中，我们依赖于。最后，我们和其他人也认为这些突变会影响核小体结构和/或完整性。确定了 EZHIP 蛋白的新功能，该蛋白在后颅窝 A 室管膜瘤中过度表达，并且作为癌组蛋白模拟物，直接抑制 Polycomb 抑制复合物 2 (PRC2) 功能。我们计划的目标是阐明经典和新颖的“癌组蛋白”背后的分子机制突变和癌组蛋白模拟物以推进癌症的诊断和治疗途径的探索具体来说，我们将： i) 开发和采用基于患者样本、细胞培养和动物模型的新型药物。概括肿瘤组蛋白相关癌症并研究潜在致病机制的系统； ii) 使用以下方法评估一组综合的新型癌症相关组蛋白突变的活性：多学科方法，包括遗传学（条形码癌组蛋白库、小鼠模型、条形码细胞系）、表观遗传学（ChIP-seq、ATAC-seq、DNA 甲基化分析）、转录组学 (RNA-seq) 和化学生物学（“设计染色质”、小分子抑制剂）；iii) 定义癌组蛋白的机制，以及癌组蛋白模拟物，失调多梳抑制复合物（PRC1 和 PRC2）活性以促进神经胶质瘤和骨肿瘤；以及 iv) 确定哪些新的组蛋白突变扰乱染色质状态（并通过什么机制）随后使用新开发的高通量引起细胞表型这些研究将为未来的开发工作提供信息。旨在改善组蛋白突变和癌组蛋白致病作用的治疗策略模仿癌症。