CAREER: Molecular Dissection of Arabidopsis DNA Methylation Mechanism

在植物和哺乳动物等复杂的基因组中，DNA是通过甲基的化学加成来选择性地修饰的。这项研究的目标是了解使DNA甲基化的酶如何定位要修改的正确位置。这是一个重要的问题，因为准确的甲基化沉积对基因组的完整性和功能至关重要，甲基化的变化可能导致异常的发育和病理状态，包括癌症。该项目的科学成果最终可能被证明有助于开发纠正甲基化缺陷的新技术，从而改善农业和医药。此外，该项目将提供许多教育好处，例如为本科生、研究生和博士后提供多学科研究培训，包括来自代表性不足群体的培训。该项目还将吸引高中生参与研究，目的是提供丰富的体验，特别是为女性、少数民族和那些将成为家庭中第一个上大学的人。该项目的另一个影响将是开发三个以遗传学各个方面为中心的学习模块：K-12学生的桌面科学站，中学生的野外旅行模块，以及威斯康星州农村高中学生和科学教师的夏令营。DNA甲基化不仅在植物、真菌和一些动物中普遍存在，而且在这些生物的基因组防御、分化、发育、疾病和环境反应中发挥关键作用。尽管它很重要，但人们对建立细胞类型和位点特异性DNA甲基化的实际线索和分子机制知之甚少。要了解DNA甲基化的不同功能，需要了解DNA甲基转移酶--这种修饰的核心酶--是如何针对特定基因组基因座的机械知识。本项目以拟南芥为模型，重点研究了几种新的染色质因子在调节全基因组DNA甲基化模式的建立和维持中的分子作用。该项目中提出的全面的遗传、生化和基因组研究将在整个基因组水平和局部DNA序列水平产生对DNA甲基化调节的特异性的重要机械性见解。深入的DNA甲基化机理知识对于理解在生理和病理条件下建立DNA甲基化景观的分子过程至关重要。这项研究还将对理解DNA甲基化如何与其他关键的发育、生理和环境过程相协调，以调节其他动植物物种的基因组功能产生重大影响。

In complex genomes like those in plants and mammals, the DNA is selectively modified by chemical addition of methyl groups. The goal of this research is to understand how enzymes that methylate DNA locate the correct sites to modify. This is an important question, because accurate methylation deposition is critical for genome integrity and function, and alterations in methylation can result in abnormal developmental and pathological states, including cancers. The scientific outcome of this project could ultimately prove useful for developing novel technologies to correct methylation defects and thereby to improve agriculture and medicine. In addition, this project will provide many educational benefits, such as multi-disciplinary research training for undergraduate students, graduate students and postdocs, including those from underrepresented groups. The project will also engage high school students in research, with the aim of providing an enriching experience, particularly for women, minorities, and those who would be the first in their families to attend college. Another impact of the project will be the development of three learning modules centered on various aspects of genetics: tabletop science station for K-12 students, field trip module for middle school students, and summer science-camp for rural Wisconsin high school students and science teachers.DNA methylation is not only prevalent in plants, fungi, and some animals, but also plays critical roles in genome defense, differentiation, development, disease, and environmental responses in these organisms. Despite its importance, remarkably little is known about the actual cue and the molecular mechanism that establish cell type- and locus-specific DNA methylation. Understanding the diverse functions of DNA methylation requires mechanistic knowledge of how DNA methyltransferase, the enzyme at the heart of this modification, is targeted to specific genomic loci. This project focuses on understanding the molecular actions of several new chromatin factors in mediating the establishment and maintenance of genome-wide and locus-specific DNA methylation patterns, using Arabidopsis thaliana as a powerful model. The comprehensive genetic, biochemical, and genomic studies proposed in this project will generate significant mechanistic insights into the specificity of DNA methylation regulation at the whole genome levels as well as local DNA sequence levels. Deep mechanistic knowledge of DNA methylation is crucial to understanding the molecular processes that establish DNA methylation landscapes under physiological and pathological conditions. This research will also have substantial impacts on understanding how DNA methylation is coordinated with other critical developmental, physiological, and environmental processes to regulate genome function in other plant and animal species.