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

• 批准号: 9904665
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904665
• 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; 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; outcome forecast; promoter; response; stem; transcription factor; transcription factor S-II; tumor; tumor progression

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/文摘