Uncovering the epigenetic codes for genome integrity, developmental and environmental interaction.

揭示基因组完整性、发育和环境相互作用的表观遗传密码。

• 批准号: 10223356
• 负责人: XUEHUA ZHONG
• 金额: $ 37.61万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223356
• 关键词: Angiosperms; Animal Model; Animals; Arabidopsis; Biological Models; Biological Process; Caenorhabditis elegans; Chemicals; Chromatin; Code; Common Core; Cytosine; DNA Methylation; Defect; Deposition; Development; Developmental Process; Disease; Drosophila melanogaster; Epigenetic Process; Genome; Human; Knowledge; Malignant Neoplasms; Mammals; Medicine; Modification; Molecular; Organism; Pathologic; Pathologic Processes; Pattern; Phase Transition; Physiological; Physiological Processes; Play; Public Health; Regulator Genes; Research; Role; Saccharomyces cerevisiae; Stimulus; Switch Genes; System; Tissues; epigenetic regulation; genome integrity; insight; null mutation; programs; public health relevance; response

PROJECT SUMMARY Epigenetic modification is an important gene regulatory mechanism and plays quintessential roles in the control of genome integrity, development, environmental responses, and diseases. Despite the large amount of studies describing altered modification patterns in abnormal developmental and pathological tissues, whether they are a cause or a consequence is poorly understood. This proposal dissects molecular mechanism of epigenetic regulation and functional consequences of altered epigenetic patterns under physiological conditions. Specifically, we investigate 1) how chromatin senses and memorizes the environmental stimuli; 2) how an epigenetic switch regulates developmental phase transition; and 3) how epigenetic modification safeguards the genome integrity. We use the flowering plant Arabidopsis, proved to be a robust system for mechanistic epigenetic studies, as our model system. Arabidopsis shares with mammals the common core cytosine DNA methylation machinery that is lacking in other model organisms (e.g. Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster). Importantly, Arabidopsis tolerates null mutations in most epigenetic regulators that are often lethal in animals, providing a significant advantage to investigate in-depth mechanisms under developmental and physiological conditions. As we probe basic principles governing epigenetic regulation that are conserved across eukaryotic organisms, knowledge acquired from our pioneering studies in Arabidopsis will help accelerate progress in deciphering the relevant mechanisms in human. In-depth mechanistic knowledge is crucial for understanding how epigenetic modification contributes to developmental defects and disease. Such knowledge will provide the necessary insight to develop new medicines that target the respective epigenetic processes.

项目摘要 表观遗传修饰是一种重要的基因调节机制，在 控制基因组完整性，发展，环境反应和疾病。尽管有 大量研究描述了异常发育和 病理组织，无论是原因还是后果。这个建议 解剖表观遗传调节的分子机制和改变的功能后果 生理条件下的表观遗传模式。具体而言，我们研究1）染色质如何 感官并记住环境刺激； 2）表观遗传开关如何调节 发育相变； 3）表观遗传修饰如何保护基因组完整性。 我们使用开花植物拟南芥，被证明是机械表观遗传的强大系统 研究，作为我们的模型系统。拟南芥与哺乳动物共同核心胞嘧啶DNA 其他模型生物中缺乏的甲基化机制（例如酿酒酵母， 秀丽隐杆线虫和果蝇Melanogaster）。重要的是，拟南芥可容忍无效 大多数表观遗传调节剂中通常致命的动物的突变，提供了重要的 在发育和生理条件下研究深入机制的优势。作为 我们探究了跨真核的基本原理 有机体，从我们在拟南芥的开创性研究中获得的知识将有助于加速 在人类中解密相关机制方面的进展。深入的机械知识是 对于了解表观遗传修饰如何有助于发育缺陷和 疾病。这些知识将提供必要的见解，以开发针对的新药物 各自的表观遗传过程。