Establishment and Modulation of DNA Methylation Patterns in Arabidopsis

描述(申请人提供)：DNA及其相关的组蛋白是染色质的两个主要组成部分，它们共同组织细胞内的遗传信息，并作为大量基本细胞生物学的背景，包括DNA复制、转录、重组和修复。然而，染色质并不是一成不变的，它是通过在DNA和/或组蛋白上添加各种称为染色质修饰的化学标签来改变的。DNA甲基化就是这样一种修饰，它与基因沉默有关，并在包括印迹、细胞分化和维持基因组完整性在内的各种生物过程中发挥重要作用。然而，我们对特定的DNA甲基化模式是如何建立的，以及它们是如何导致基因沉默的了解很少。了解DNA甲基化的这些方面不仅对于理解正常的过程至关重要，而且对于理解甲基化模式的变化如何导致发育缺陷和疾病的进展也是至关重要的。这项建议的重点是了解几个新发现的蛋白质复合体在植物模型拟南芥中的作用。这些复合体被认为通过调节染色质结构在促进基因沉默方面发挥关键作用，并在建立DNA甲基化的位点和/或细胞类型特异性模式方面发挥关键作用。这些研究的目标是将DNA甲基化与染色质的变化机械地联系起来，这些变化不利于基因表达，并将DNA甲基化机制的特定组成部分分配给独特的DNA甲基化模式。总之，这些发现将扩大我们对DNA甲基化、基因沉默和发育程序如何耦合的知识--这是正常生长和发育的关键过程，当中断时，会导致急性和慢性疾病。拟南芥是研究表观遗传过程的理想系统，如DNA甲基化，因为它具有遗传可塑性，具有高度服从全基因组分析的小基因组，并且对表观遗传格局的戏剧性变化具有耐受性。此外，参与建立和维持表观遗传修饰的许多关键角色和途径在植物和哺乳动物之间是保守的。因此，对形成DNA甲基化图谱的机制的理解，以及对DNA甲基化如何影响植物转录等下游过程的理解，将适用于哺乳动物的类似过程。

DESCRIPTION (provided by applicant): DNA and its associated histones are the two main components of chromatin and together they organize the genetic information within the cell and serve as a backdrop for a vast array of essential cell biology including DNA replication, transcription, recombination and repair. However chromatin is not static, it is altered by the addition of various chemical tags, termed chromatin modifications, to DNA and/or histones. One such modification, DNA methylation, is associated with gene silencing and plays important roles in diverse biological processes including imprinting, cellular differentiation and the maintenance of genome integrity. Yet, our understanding of how specific DNA methylation patterns are established and how they lead to gene silencing is poorly understood. Gaining insight into these facets of DNA methylation will be critical not only in understanding normal processes but also in understanding how alterations in methylation patterns can lead to developmental defects and the progression of diseases. This proposal focuses on understanding the roles of several newly identified protein complexes in the plant model Arabidopsis thaliana. These complexes are proposed to play key roles in facilitating gene silencing by modulating chromatin structure and in establishing locus- and/or cell type-specific patterns of DNA methylation. The goals of these studies are to mechanistically connect DNA methylation to changes in chromatin that are refractory to gene expression and to assign specific components of the DNA methylation machinery to unique DNA methylation patterns. Together, these findings will expand our knowledge of how DNA methylation, gene silencing, and developmental programs are coupled-a critical process for normal growth and development that when disrupted contributes both acute and chronic diseases. Arabidopsis is an ideal system to study epigenetic processes, like DNA methylation, as it is genetically malleable, has a small genome that is highly amenable to genome-wide analyses, and is tolerant of dramatic changes in its epigenetic landscape. In addition, many of the key players and pathways involved in establishing and maintaining epigenetic modifications are conserved between plants and mammals. Thus, understanding of the machinery that shapes DNA methylation profiles and in turn, understanding of how DNA methylation influences downstream processes like transcription in plants, will be applicable to analogous processes in mammals.