Mechanisms Regulating DNA Methylation Maintenance in Chromatin

染色质 DNA 甲基化维持的调节机制

• 批准号: 9061649
• 负责人: Scott Rothbart
• 金额: $ 24.87万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9061649
• 关键词: Aberrant DNA Methylation; Address; Affect; Attention; Binding; Biological; Biological Process; Biology; Cancerous; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Chemicals; Chromatin; Chromatin Structure; Colonic Neoplasms; CpG dinucleotide; DNA; DNA Damage; DNA Methylation; DNA Methylation Regulation; DNA Modification Methylases; DNA Repair; DNA biosynthesis; Daughter; Defect; Dependence; Development; Epigenetic Process; Foundations; Functional disorder; Genetic Transcription; Genomics; Goals; Histone Code; Histone H3; Histones; Human; Human Engineering; Human Genome; Hypersensitivity; In Vitro; Learning; Link; Lysine; Maintenance; Malignant - descriptor; Malignant Neoplasms; Maps; Mentorship; Neoplasm Metastasis; Pattern; Plants; Post-Translational Protein Processing; Proteins; Reading; Research; Resolution; Role; S Phase; Solid; Switch Genes; Systems Biology; Therapeutic; Training; Tumor Cell Line; Tumor Suppressor Genes; Uncertainty; Validation; Writing; cancer cell; cancer initiation; cancer prevention; cancer therapy; career; cellular targeting; epigenetic regulation; genetic information; homeodomain; inhibitor/antagonist; methylation pattern; non-histone protein; programs; protein protein interaction; screening; small molecule inhibitor; therapeutic target; tool; tumor progression; ubiquitin-protein ligase

PROJECT SUMMARY/ABSTRACT DNA methylation and histone post-translational modifications (PTMs) elicit influence on chromatin-templated biological processes, and these `epigenetic' marks are often aberrantly regulated in cancers. Elucidation of mechanisms controlling DNA methylation and histone PTMs are therefore important to better our understanding of the role of epigenetics in cancer. The E3 ubiquitin ligase UHRF1 is genetically linked to the maintenance of cellular DNA methylation and deregulation of UHRF1 correlates with cell proliferation, metastasis, and hypersensitivity to DNA damaging agents. These recent connections of UHRF1 to the regulation of DNA methylation and cancer progression suggest this protein may be a favorable therapeutic target. Yet, many fundamental aspects of UHRF1 biology are not known. The overarching goal of this K99/R00 proposal is therefore to advance our understanding of the interaction of UHRF1 with chromatin and the regulation of DNA methylation inheritance. My preliminary studies established that recognition of methylated histone H3 at lysine 9 by the UHRF1 tandem Tudor domain is required for its DNA methylation maintenance function. Studies in this proposal will build upon these findings to: 1) define how multivalent chromatin engagement drives the DNA methylation maintenance function of UHRF1, 2) determine the spatial and temporal contribution of UHRF1 to DNA methylation maintenance, 3) define the UHRF1 interactome, and 4) develop chemical probes as tools to study UHRF1 function. This proposal is supported by a strong mentorship and training plan, building a solid foundation for a successful independent research career investigating the regulation of the epigenetic program and how its dysfunction leads to the initiation and progression of cancer.

项目摘要/摘要 DNA甲基化和组蛋白翻译后修饰（PTMS）引起对染色质 - 模拟的影响 生物学过程和这些“表观遗传学”标记通常在癌症中受到异常调节。阐明 因此，控制DNA甲基化和组蛋白PTM的机制对于改善我们的 了解表观遗传学在癌症中的作用。 E3泛素连接酶UHRF1与 维持细胞DNA甲基化和UHRF1的放松管制与细胞增殖相关， 转移和对DNA损伤剂的过敏性。 UHRF1的这些最近连接 DNA甲基化和癌症进展的调节表明该蛋白可能是一种有利的治疗方法 目标。然而，UHRF1生物学的许多基本方面尚不清楚。此K99/R00的总体目标 因此，建议是为了促进我们对UHRF1与染色质和染色质和 DNA甲基化遗传的调节。我的初步研究确定了对甲基化的认识 UHRF1串联TUDOR结构域在赖氨酸9处的组蛋白H3是其DNA甲基化维持所必需的 功能。该提案中的研究将基于以下发现的基础：1）定义多价染色质 参与驱动UHRF1的DNA甲基化维持函数，2）确定空间和 UHRF1对DNA甲基化维持的时间贡献，3）定义UHRF1相互作用组，4） 开发化学探针作为研究UHRF1功能的工具。该建议得到了强有力的指导支持 和培训计划，为成功的独立研究职业奠定了坚实的基础，调查了 表观遗传程序的调节及其功能障碍如何导致癌症的启动和进展。