Project 3: Mechanisms of Methyltransferase Dysregulation by Oncohistones

项目 3：肿瘤组蛋白甲基转移酶失调的机制

基本信息

批准号：
10024845
负责人：
Tom Muir
金额：
$ 27.1万
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/10024845
关键词：
3-Dimensional Address Affect Alleles Architecture Bar Codes Biochemical Biochemical Genetics Biochemical Process Biological Biology Biophysics Categories Cell Culture System Cell Survival Chemicals Chemistry Chromatin Chromatin Structure Collaborations Collection DNA Data Databases Deposition Disease Epigenetic Process Excision Funding Future Genes Genetic Screening Genetic Transcription Genome Genomic DNA Genomic approach Genomics Globular Region Goals Histone Fold Histone H3 Histones Human Investigation Lead Libraries Malignant Childhood Neoplasm Malignant Neoplasms Methods Methyltransferase Missense Mutation Modification Molecular Mutation N-terminal Nucleosomes Output Phase Phenotype Physiological Polymers Post-Translational Protein Processing Process Proteins Proteomics Regulation Role Screening Result Screening procedure Signal Transduction Structure Tail Technology Testing Therapeutic Trans-Activators Transcriptional Regulation Validation Work Yeasts base biophysical properties cancer cell cancer type chromatin remodeling design dimer falls genome integrity high throughput screening in vivo evaluation knowledge base member mouse model mutant programs screening success tool tumor tumorigenesis yeast genetics

项目摘要

PROJECT SUMMARY SUMMARY: The broad goal of this project is to study the detailed molecular mechanisms by which histone mutations associated with cancers perturb chromatin states, leading to disease. The next phase of this program is driven by our recent work with the Allis lab revealing a vastly expanded landscape of putative oncohistone mutations - over 4200 missense mutations in dozens of human cancers. Remarkably, the mutations occur in all four of the core histones and in both the N-terminal tails and globular histone fold domains. The very large number of newly identified oncohistones makes experimental characterization daunting. A key challenge is to identify those mutations that act as potential cancer drivers from those that are merely a consequence of the high mutation burden of a given tumor (i.e. passengers). We will work closely with other members of the P01 team to identify those mutations that most likely to fall into the former category and that, as such, merit in vivo testing. Strategically, we will approach this problem using newly developed high-throughput biochemical and yeast genetic screening tools (Aim 1) that are expected to identify mutations that alter chromatin stability and/or that affect the activity of trans-acting factors that operate on the chromatin polymer. Validation of the ‘hits’ from the screening studies will form the core of Aims 2 & 3 where we will combine the use of chemically-defined chromatin templates with biochemical, proteomic and genomic approaches to develop a mechanistic understanding of how select mutations impact chromatin state. In particular, we will study how breakdown in nucleosome symmetry, as a result of sub-stoichiometric incorporation of mutant histones, affects key processes such as chromatin remodeling and transcription. We imagine that many of the technologies developed in the context of this work will have broad utility in the epigenetics field generally. Ultimately, the biochemical knowledge base generated in the course of this program will motivate future therapeutic efforts for treating cancers associated with oncohistone mutants.

项目摘要摘要：该项目的广泛目标是研究组蛋白的详细分子机制与癌症烧焦染色质状态相关的突变，导致疾病。该程序的下一个阶段我们最近与Allis Lab的工作所驱动的，揭示了Putative on Charistone的广泛扩展的景观突变 - 数十个人类癌症中超过4200个错义突变。值得注意的是，这些突变发生在所有人中四个核心组蛋白以及N末端尾部和全局组蛋白折叠域中。很大在酒精酮上的新鉴定的数量使实验表征令人生畏。一个关键挑战是从仅仅是仅仅是结果的结果，从给定肿瘤的高突变燃烧（即密码）。我们将与P01的其他成员紧密合作团队确定最有可能属于前者类别的突变，因此在体内值得测试。从战略上讲，我们将使用新开发的高通量生化和酵母基因筛查工具（AIM 1）有望识别改变染色质稳定性和/或的突变这会影响在染色质聚合物上作用的跨作用因子的活性。从筛选研究将构成目标2和3的核心，我们将结合化学定义的使用具有生化，蛋白质组学和基因组方法的染色质模板来开发机械了解选择突变如何影响染色质状态。特别是，我们将研究如何分解核小体对称性是由于突变组蛋白的亚化学计量学的结果，影响关键过程例如染色质重塑和转录。我们认为许多技术在这项工作的背景通常在表观遗传学领域具有广泛的效用。最终，生化知识该计划过程中产生的基础将激发未来的治疗努力治疗癌症与酒精酮突变体相关。