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Mechanisms of chromatin remodeling at RNA polymerase II promoters

RNA聚合酶II启动子的染色质重塑机制

基本信息

批准号：
10361209
负责人：
Edward E Luk
金额：
$ 33.22万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10361209
关键词：
ATP phosphohydrolase Affinity Binding Biochemical Biological Assay Biological Process Cancer Patient Cell Proliferation Cell physiology Cells Chromatin Chromatin Structure Chromosome Structures Complex DNA DNA Structure Defect Deposition Development Enzymes Event Funding Gene Expression Genes Genetic Transcription Grant Histone Fold Histone H2A Histones Human In Vitro Knowledge Lead Link Malignant Neoplasms Methods Molecular Molecular Chaperones Motor Mutate Mutation Normal Cell Nucleosomes Orthologous Gene Outcomes Research Paper Pathway interactions Phosphorylation Phosphotransferases Prognosis Property Proteins RNA Polymerase II Reaction Role Saccharomycetales Site Structure TAF1 gene Testing Therapeutic Intervention Tissues Ursidae Family Work Yeast Model System Yeasts cancer cell chromatin remodeling craniofacial development dimer driving force gene function in vitro activity in vivo molecular drug target mutant new therapeutic target novel promoter response stem transcription factor transcription factor S-II tumor tumor progression

项目摘要

7. PROJECT SUMMARY/ABSTRACT A fundamental aspect of all biological processes is gene expression, which is controlled at a variety of levels, the first step being transcription. Transcription is regulated not only by sequence-specific factors such as activators and repressors, but also by the underlying chromatin structure of the chromosomal DNA. This structure is determined by various chromatin remodeling pathways. Genes encoding regulators of chromatin remodeling pathways are frequently mutated in human cancers. Perturbation of chromatin regulators promotes cancer progression in part by reverting the `on' or `off' chromatin states committed during tissue development to a poised, stem-like state, thereby increasing gene expression plasticity that enables cancer cells to evolve and adapt. Histone H2A.Z is an important chromatin regulator that poises genes for transcription. It is inserted into nucleosomes immediately downstream of the promoters of most genes. Hyper-accumulation of H2A.Z makes cancer cells more invasive and is linked with poor prognosis in cancer patients. Using the budding yeast model system, I previously demonstrated that the highly conserved, ATP- dependent remodeler SWR replaces nucleosomal H2A with H2A.Z in a unidirectional manner in vitro. During the current funding period, my lab found that H2A.Z is subjected to rapid turnover at both actively and infrequently transcribed genes and that the transcription machinery targets H2A.Z nucleosomes for disassembly in vivo. In addition, we developed a novel method for globally determining the levels of H2A.Z and H2A-containing nucleosomes in yeast and human cells called VivosX. This proposal will extend this work to (1) dissect the molecular mechanisms by which the SWR chromatin remodeling enzyme inserts H2A.Z into specific sites on chromatin and (2) elucidate the molecular events at promoters after H2A.Z insertion. This knowledge may ultimately reveal molecular targets for drugs that can counteract the aberrant levels of H2A.Z in cancer cells.

7.项目总结/摘要所有生物学过程的一个基本方面是基因表达，其在多种生物学过程中受到控制。第一步是转录。转录不仅受到序列特异性因子的调控，作为激活子和抑制子，但也通过染色体DNA的潜在染色质结构。这结构由各种染色质重塑途径决定。编码染色质调节因子的基因人类癌症中重塑途径经常发生突变。染色质调节因子的扰动促进癌症进展部分是通过恢复组织发育过程中所承诺的“开”或“关”染色质状态从而增加基因表达的可塑性，使癌细胞能够进化并适应。组蛋白H2A.Z是一种重要的染色质调节因子，其使基因转录平衡。其插入进入大多数基因启动子下游的核小体。H2A.Z超积累使癌细胞更具侵袭性，并与癌症患者的预后不良有关。使用芽殖酵母模型系统，我以前证明了高度保守的ATP- 依赖性重塑体SWR在体外以单向方式用H2A.Z取代核小体H2 A。期间在当前的资金周期内，我的实验室发现H2A.Z在积极和积极的方面都面临着快速的流动，不经常转录的基因，转录机制靶向H2A.Z核小体，体内解体此外，我们开发了一种新的方法，用于全球确定H2A.Z和酵母和人类细胞中含有H2 A的核小体，称为VivosX。本建议将这项工作扩展到（1）剖析了SWR染色质重塑酶将H2A.Z插入染色质上的特异性位点和（2）阐明H2A.Z插入后启动子处的分子事件。这这些知识可能最终揭示出能够抵消H2A.Z异常水平的药物的分子靶点。在癌细胞中。