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

• 批准号: 10024842
• 负责人: CHARLES DAVID ALLIS
• 金额: $ 179.05万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 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/10024842
• 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 Methylation; DNA Repair; 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; overexpression; programs; small molecule inhibitor; theories; therapeutic development; transcriptome sequencing; transcriptomics; tumor; tumorigenesis; tumorigenic; yeast genetics

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.

项目摘要（总体） 染色质景观会影响基本细胞过程，包括基因表达，DNA损伤 修复，细胞命运和分化，所有这些都在癌症中广泛失调。集体数字 染色质调节剂中的致癌突变导致了驱动突变的新兴视野 癌症的表观观念。为了与主题保持一致，在过去的几年中，我们当前的协作计划 成员对在酒精酮突变中的发现和表征至关重要 Hisstone H3.3 N末端尾巴。这些突变通过抑制染色质的活性来改变染色质 修饰酶。尽管已经取得了很大的进步来理解这些效果，但重要的问题 保留包括通过这些突变修饰酶的染色质修饰酶的性质的性质以及如何 这些突变导致癌症。此外，计划成员最近确定了扩大的数量 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，并且涉及两者 所有四个核心组蛋白的全球和尾部域。这些发现产生了其他重要问题 好像新观察到的组蛋白突变对染色质具有功能作用以及通过哪些机制 他们依靠。鉴于一些最普遍的突变是在组蛋白的全球域中，我们 假设这些突变会影响核小体的结构和/或完整性。最后，我们和其他人也有 确定了Ezhip蛋白的新功能，该蛋白在后窝A d膜瘤中过表达，并且 充当酒精酮模仿，直接抑制多孔抑制复合物2（PRC2）函数。单人 我们程序的目标是阐明经典和新颖的“酒精酮”的分子机制 突变和酒精酮模仿，以促进对治疗途径的诊断和探索 癌症。具体来说，我们将：i）开发和员工新型患者样品，细胞培养和基于动物模型 概括与酒精酮相关的癌症并研究潜在的致病机制的系统； ii）评估使用A的一组综合癌症相关组蛋白突变的全面活性 多学科方法，包括遗传学（酒精酮库，鼠标模型，条形码细胞的条形码 线条，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（“设计师染色质”，小分子抑制剂）； iii）定义了饮料酮的机制，并定义 关于酒精酮模仿，使Polycomb抑制复合物（PRC1和PRC2）活性失调以促进 神经胶质瘤和骨肿瘤；和iv）确定哪种新型组蛋白突变均匀染色质状态（以及通过 什么机制）随后使用新开发的高通量引起细胞表型 生化和酵母基因筛查工具。这些研究将为未来的发展提供依据 旨在改善组蛋白突变和酒精酮的致病作用的治疗策略 模仿癌症。