Molecular mechanisms of chromatin and epigenetic regulation

染色质和表观遗传调控的分子机制

• 批准号: 9381318
• 负责人: Scott Rothbart
• 金额: $ 47.5万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381318
• 关键词: Age; Biochemical; Biology; Biophysics; Cells; Chromatin; Complex; DNA Methylation; DNA Methylation Regulation; Development; Environment; Epigenetic Process; Genes; Genome; Goals; Histone H3; Histones; Knowledge; Mammalian Cell; Molecular; Nuclear Proteins; Pathway interactions; Plant Roots; Post-Translational Protein Processing; Process; Proteins; Proteomics; Reader; Regulation; Research; Role; Signal Transduction; Therapeutic; Time; Translating; Ubiquitination; base; chromatin modification; drug discovery; epigenetic regulation; human disease; interest; multidisciplinary; programs; response; structural genomics; ubiquitin-protein ligase

PROJECT SUMMARY The long-term goal of our research program is to define molecular mechanisms regulating chromatin modification signaling. We are particularly interested in understanding the complex relationship between DNA methylation and histone posttranslational modifications; two key epigenetic regulators of genome accessibility and function. Within this broad framework, we question 1) how are the writers and erasers of chromatin modifications regulated, 2) how do nuclear proteins and their complexes interface with (i.e., read) epigenetic marks to perform their chromatin regulatory functions, and 3) how does deregulation of chromatin signaling contribute to human disease? Our current studies are focused on UHRF1, an E3 ubiquitin ligase that is the cornerstone of a pathway responsible for maintaining a major portion of the DNA methylation found in mammalian cells. We recently showed that UHRF1 functions as a key regulator of DNA methylation inheritance through its interconnected reader and writer activities toward histone H3. While details of how UHRF1 performs its regulatory function are beginning to be uncovered, major gaps in knowledge exist in our basic molecular understanding of DNA methylation regulation and the role of UHRF1 in this process. Projects in the lab under this framework will question 1) how does UHRF1 interact with and modify chromatin, 2) what is the relationship between UHRF1, DNA methylation, and genome accessibility, 3) what is the role of histone ubiquitination in DNA methylation regulation, and 4) how does the structurally related protein UHRF2 regulate DNA methylation? Through a multidisciplinary and collaborative research program that leverages strengths in biochemical, biophysical, structural, genomic, proteomic, and cell-based studies of chromatin and epigenetic regulation, we hope to translate basic knowledge of epigenetic mechanism into therapeutic benefit.

项目摘要 我们研究计划的长期目标是确定调控染色质的分子机制 修改信令我们对了解DNA之间的复杂关系特别感兴趣 甲基化和组蛋白翻译后修饰;基因组可及性的两个关键表观遗传调节因子 和功能在这个广泛的框架内，我们的问题1）如何染色质的作家和擦除器 调节的修饰，2）核蛋白及其复合物如何与（即，读）表观遗传的 标记来执行它们的染色质调节功能，以及3）染色质信号转导的失调如何 会导致人类疾病吗我们目前的研究集中在UHRF 1，一种E3泛素连接酶，是一种在细胞内表达的蛋白质。 这是一个负责维持大部分DNA甲基化的途径的基石， 哺乳动物细胞我们最近发现，UHRF 1作为DNA甲基化的关键调节因子发挥作用， 遗传通过其相互关联的读者和作家活动向组蛋白H3。虽然细节如何 UHRF 1执行其监管功能的情况开始被发现，我们的知识存在重大差距， DNA甲基化调控的基本分子理解和UHRF 1在这一过程中的作用。项目 在这个框架下的实验室中，将提出以下问题：1）UHRF 1如何与染色质相互作用并修饰染色质，2） UHRF 1、DNA甲基化和基因组可及性之间的关系，3）组蛋白的作用是什么 DNA甲基化调控中的泛素化，以及4）结构相关蛋白UHRF 2如何调节 DNA甲基化？通过多学科和合作研究计划，利用优势， 染色质和表观遗传的生物化学、生物物理学、结构、基因组学、蛋白质组学和基于细胞的研究 调控，我们希望将表观遗传机制的基础知识转化为治疗益处。