Structural Studies of Transcriptional Silencing

转录沉默的结构研究

• 批准号: 7578875
• 负责人: RUI-MING XU
• 金额: $ 42.06万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7578875
• 关键词: Address; Age; Antineoplastic Agents; Biology; Cells; Chromatin; Development; Dosage Compensation (Genetics); Enzymes; Epigenetic Process; Family; Funding; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genomics; Goals; Heterochromatin; Higher Order Chromatin Structure; Histone Code; Histone Deacetylase; Histone H4; Histones; Human; Knowledge; Lysine; Maintenance; Malignant Neoplasms; Mating Types; Mating-Type Genes; Methyltransferase; Molecular; Mutation; Nucleosome Core Particle; Play; Polycomb; Proteins; Reagent; Recruitment Activity; Regulation; Research; Resolution; Role; Saccharomyces cerevisiae; Structure; Substrate Specificity; Therapeutic Agents; X Inactivation; X-Ray Crystallography; Yeasts; base; histone methyltransferase; histone modification; insight; protein structure; small molecule; tool

DESCRIPTION (provided by applicant): Epigenetic control of gene expression plays important roles in eukaryotic biology. Examples of epigenetic regulation include control of Hox gene expression during development and in differentiated cells, dosage compensation and aging. Many cancers are associated with altered epigenetic regulation, which involves the assembly of higher order chromatin structures. This proposal focuses on studying the molecular mechanisms by which higher order chromatin structures are established and maintained. We use X-ray crystallography as our main tool to study mechanisms by which epigenetic regulators are recruited to the silent genomic loci, structures and functions of histone modification enzymes, and the recognition of histone codes. We will study in parallel the genetically well-characterized mating-type silencing in S. cerevisiae and chromatin-associated proteins in humans. The study should provide mechanistic understanding of heterochromatin assembly in yeast, as well as providing important insights into mechanisms of epigenetic regulation of gene expression in humans. The atomic-resolution structures may also be used to aid the development of therapeutic agents against cancer.

描述（由申请人提供）：基因表达的表观遗传控制在真核生物学中发挥着重要作用。表观遗传调控的例子包括发育过程中和分化细胞中Hox基因表达的控制、剂量补偿和衰老。许多癌症与表观遗传调控的改变有关，这涉及高级染色质结构的组装。该提案重点研究建立和维持高级染色质结构的分子机制。 我们使用 X 射线晶体学作为主要工具来研究表观遗传调节因子被招募到沉默基因组位点的机制、组蛋白修饰酶的结构和功能以及组蛋白密码的识别。我们将同时研究酿酒酵母中具有良好遗传特征的交配型沉默和人类染色质相关蛋白。这项研究应该提供对酵母中异染色质组装的机制理解，并为人类基因表达的表观遗传调控机制提供重要见解。原子分辨率结构还可用于帮助开发抗癌治疗剂。