STRUCTURAL STUDY OF EPIGENETIC MODIFICATIONS

表观遗传修饰的结构研究

• 批准号: 8361728
• 负责人: Xiaodong Cheng
• 金额: $ 0.55万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361728
• 关键词: Aging-Related Process; Binding; Chromatin Structure; Complex; DNA; DNA Methylation; DNA biosynthesis; Degenerative Disorder; Enzymes; Epigenetic Process; Funding; Gene Activation; Gene Expression Regulation; Genes; Grant; Histone Code; Histone H3; Histones; Lysine; Malignant Neoplasms; Modeling; Modification; National Center for Research Resources; Nucleosomes; Outcome; Play; Principal Investigator; Proteins; Reader; Research; Research Infrastructure; Resources; Role; Source; Stem Cell Development; United States National Institutes of Health; cellular pathology; cost; enzyme structure; histone modification; new therapeutic target; recombinational repair; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Epigenetic modifications, including DNA methylation, histone covalent modifications and ATP-dependent remodeling of nucleosomes, interact to play a fundamental role in the regulation of gene expression and DNA replication, recombination and repair, and they are responsible for stem cell development and differentiation. Importantly, these modifications impact the aging process and a number of cellular pathologies, such as cancers and degenerative diseases. Histone modifications serve as the binding platform for effector proteins or complexes that alter the structure of chromatin and modulate gene activity. The histone code hypothesis posits that specific modifications or combinations thereof dictate specific outcomes associated with a particular chromatin structure (heterochromatic vs euchromatic) and gene activation state. The model predicts that these modifications create targets that can be recognized by effector molecules. As such, enzymes that catalyze the modifications have been termed writers, those that recognize the marks, readers; and finally, erasers are enzymes that remove such marks from histones. Importantly, such enzymes and binding modules are novel targets for therapeutics. The overriding aim of this project is therefore to generate a sspectrum of structures for enzymes modifying DNA and histone H3 lysines 4, 9, 27, and 36, respectively.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 表观遗传修饰包括DNA甲基化、组蛋白共价修饰和核小体的ATP依赖性重塑，它们相互作用，在基因表达调控和DNA复制、重组和修复中发挥重要作用，并对干细胞的发育和分化起重要作用。 重要的是，这些修饰影响衰老过程和许多细胞病理学，如癌症和退行性疾病。 组蛋白修饰作为效应蛋白或复合物的结合平台，改变染色质的结构并调节基因活性。组蛋白密码假说假定，特定的修饰或其组合决定了与特定染色质结构（异染色质与常染色质）和基因激活状态相关的特定结果。该模型预测，这些修饰产生了可以被效应分子识别的靶标。因此，催化修饰的酶被称为写入器，识别标记的酶被称为读取器;最后，擦除器是从组蛋白中去除这些标记的酶。重要的是，这些酶和结合模块是治疗的新靶标。 因此，本项目的首要目标是分别产生修饰DNA和组蛋白H3赖氨酸4、9、27和36的酶的结构谱。