Renewal: MIRA: Epigenetic regulation of genome integrity, environmental interaction, and inheritance

更新：MIRA：基因组完整性、环境相互作用和遗传的表观遗传调控

• 批准号: 10671739
• 负责人: XUEHUA ZHONG
• 金额: $ 42.76万
• 依托单位: WASHINGTON UNIVERSITY
• 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 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671739
• 关键词: Acceleration; Arabidopsis; Biochemical; Biological Process; CRISPR/Cas technology; Cell physiology; Chemicals; Correlative Study; Cues; DNA Sequence; Deposition; Development; Disease; Engineering; Epigenetic Process; Eukaryota; Gene Expression; Genes; Genetic; Genome; Genomics; Health; Human; Imaging Techniques; Knowledge; Maintenance; Mediating; Medicine; Modification; Molecular; Organism; Pathologic; Pattern; Phase Transition; Physiological; Play; Proteomics; Public Health; Regulator Genes; Research; Resolution; Role; Shapes; Stress; Switch Genes; System; Technology; Tissues; developmental disease; epigenetic regulation; epigenome; epigenome editing; functional outcomes; genome integrity; genome-wide; innovation; live cell imaging; programs; response; tool

PROJECT SUMMARY Although the genome is a blueprint for making an organism, the epigenome (modification on the genome without DNA sequence change) governs the functional outcome of genes and ultimately shapes the organism. Epigenetic modification is a conserved and important gene regulatory mechanism and plays quintessential roles in genome integrity, development, environmental responses, and diseases. Despite the large number of correlative studies describing the altered modification patterns in abnormal developmental and pathological tissues, whether they are a cause or a consequence is poorly understood. This proposal dissects the molecular mechanism of epigenetic regulation and functional consequences of epigenome perturbation under developmental and physiological conditions. Specifically, we investigate i) how epigenome reprogramming in response to environmental cues might lead to stress adaptation; ii) how an epigenetic switch regulates developmental phase transition; and iii) how epigenetic modification safeguards the genome integrity. We will further dissect the causal roles of epigenetic marks on gene expression and develop an innovative CRISPR/Cas9-mediated cis- engineering system for epigenome editing. Our approach is highly interdisciplinary making use of the powerful Arabidopsis genetic system, high-throughput proteomics and genomics, live-cell imaging techniques, biochemical and structural tools to tackle mechanistic problems from genome-wide scale to atomic resolution. As we probe basic principles governing epigenetic regulation that are conserved across eukaryotes, the mechanistic knowledge and epigenome technologies acquired from our pioneering Arabidopsis studies will help accelerate progress in deciphering the relevant mechanisms in human. Such knowledge will lead to the development of innovative tools to correct aberrant epigenetic modifications and ultimately enable new applications for medicine and human health.

项目摘要 虽然基因组是制造生物体的蓝图，但表观基因组（对 没有DNA序列变化的基因组）控制基因的功能结果，并最终 塑造有机体。表观遗传修饰是一种保守而重要的基因调控机制 并在基因组完整性、发育、环境反应和 疾病尽管有大量的相关研究描述了改变的修饰模式， 在异常的发育和病理组织中，它们是原因还是结果， 不太了解。该提案剖析了表观遗传调控的分子机制， 发育和生理条件下表观基因组扰动的功能后果。 具体来说，我们调查i）如何表观基因组重编程响应环境线索可能 导致压力适应; ii）表观遗传开关如何调节发育阶段转变;以及 iii）表观遗传修饰如何保护基因组的完整性。我们将进一步剖析因果作用 基因表达的表观遗传标记，并开发创新的CRISPR/Cas9介导的顺式- 表观基因组编辑的工程系统。我们的方法是高度跨学科的，利用 强大的拟南芥遗传系统，高通量蛋白质组学和基因组学，活细胞成像 技术、生物化学和结构工具来解决全基因组范围内的机械问题 原子分辨率。当我们探索保守的表观遗传调控的基本原则时， 在真核生物中，从我们获得的机械知识和表观基因组技术 开拓性的拟南芥研究将有助于加速破译相关机制的进展， 人类这些知识将导致创新工具的发展，以纠正异常的表观遗传 修改，并最终使新的应用于医学和人类健康。