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Regulation of DNA methylation homeostasis in Arabidopsis

拟南芥 DNA 甲基化稳态的调控

基本信息

批准号：
8964312
负责人：
Mary Gehring
金额：
$ 38.17万
依托单位：
WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-07 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8964312
关键词：
Aberrant DNA Methylation Address Arabidopsis Base Excision Repairs Biological Biological Models Code Conflict (Psychology)Critical Pathways Cytosine DNA DNA Methylation DNA Methylation Regulation DNA Modification Methylases DNA Transposable Elements DNA glycosylase Data Development Disease Ensure Epigenetic Process Equilibrium Eukaryota Fertilization Gene Expression Gene Silencing Genes Genetic Genetic Screening Genetic Transcription Genome Genome Stability Genomic Imprinting Genomic approach Genomics Germ Cells Goals Growth and Development function Homeostasis Hypermethylation Joints Lead Light Maintenance Malignant Neoplasms Mammals Mediating Methylation Molecular Mutagenesis Mutate Mutation Pathway interactions Pattern Phenotype Plant DNA Plant Genome Plants Process RNA RNA methylation ROS1 gene Recovery Regulation Repression Research Source System Testing Tissues Transcript Transcriptional Regulation Untranslated RNA X Inactivation base demethylation epigenome epigenomics genome-wide luminescence male methylation pattern methylation testing methylome mutant novel offspring plant growth/development public health relevance reproductive development response sperm cell

项目摘要

DESCRIPTION (provided by applicant): DNA methylation is critical for essential processes including genomic imprinting, X-inactivation, transposable element silencing, and genome stability. DNA methylation patterns are the result of active DNA methylation and demethylation processes. Arabidopsis represents an excellent eukaryotic model system to dissect the functions and mechanisms of methylation and demethylation because of its facile genetics and genomics and the conservation of these processes with mammals. Arabidopsis has been a continued source of novel discoveries in the field of epigenetics. The function and regulation of DNA demethylation is under studied compared to processes that promote DNA methylation, partly because the mechanisms of active DNA demethylation have been elucidated only relatively recently. In plants, DNA demethylation is mediated by 5- methylcytosine (5-mC) DNA glycosylases that remove 5-mC from DNA by base excision repair, leading to its replacement with unmodified cytosine. Expression of the 5-mC DNA glycosylase ROS1 is significantly reduced in response to mutations in components of the maintenance methylation and RNA-directed DNA methylation (RdDM) pathways. This suggests that there is a molecular crosstalk between the methylation and demethylation pathways to achieve a cellular balance of these antagonistic enzymatic activities. The long-term goal of this research is to define the molecular mechanisms that ensure DNA methylation homeostasis during plant growth and development and to determine the functional consequences of perturbing that homeostasis. The proposed research focuses on ROS1, a locus where multiple epigenetic pathways converge to modulate DNA demethylase expression in response to global and local changes in DNA methylation. We will determine why and how ROS1 transcription is reduced in response to the disruption of the RdDM pathway. We will identify regulators of this process through a novel genetic screen that will identify genes that promote expression of ROS1 in a methylation deficient background. Finally, we will determine whether the decreased expression of ROS1 that occurs during wild type sperm development in response to reduced DNA methylation is responsible for establishing proper genome-wide DNA methylation patterns after fertilization. These efforts will significantly increase our understanding of how the activity of epigenetic pathways is modulated in response to the state of the epigenome. Our findings will be directly applicable to mammals and other eukaryotes that control their genome through DNA methylation based mechanisms.

描述（由申请人提供）：DNA 甲基化对于基因组印记、X 失活、转座元件沉默和基因组稳定性等基本过程至关重要。 DNA 甲基化模式是活跃的 DNA 甲基化和去甲基化过程的结果。拟南芥代表了一个优秀的真核模型系统，可以剖析甲基化和去甲基化的功能和机制，因为它具有简单的遗传学和基因组学以及这些过程在哺乳动物中的保守性。拟南芥一直是表观遗传学领域新发现的持续来源。与促进 DNA 甲基化的过程相比，DNA 去甲基化的功能和调控仍在研究中，部分原因是主动 DNA 去甲基化的机制最近才被阐明。在植物中，DNA 去甲基化是由 5-甲基胞嘧啶 (5-mC) DNA 糖基化酶介导的，该酶通过碱基切除修复从 DNA 中去除 5-mC，导致其被未修饰的胞嘧啶取代。 5-mC DNA 糖基化酶 ROS1 的表达因维持甲基化和 RNA 指导的 DNA 甲基化 (RdDM) 途径成分的突变而显着降低。这表明甲基化和去甲基化途径之间存在分子串扰，以实现这些拮抗酶活性的细胞平衡。这项研究的长期目标是确定确保植物生长和发育过程中 DNA 甲基化稳态的分子机制，并确定扰乱该稳态的功能后果。拟议的研究重点关注 ROS1，这是多个表观遗传途径汇聚的位点，可调节 DNA 去甲基化酶的表达，以响应 DNA 甲基化的全局和局部变化。我们将确定 ROS1 转录因 RdDM 通路破坏而减少的原因和方式。我们将通过一种新颖的基因筛选来识别这一过程的调节因子，该筛选将识别在甲基化缺陷背景下促进 ROS1 表达的基因。最后，我们将确定野生型精子发育过程中由于 DNA 甲基化减少而发生的 ROS1 表达减少是否是受精后建立适当的全基因组 DNA 甲基化模式的原因。这些努力将显着增加我们对表观遗传途径的活性如何根据表观基因组状态进行调节的理解。我们的研究结果将直接适用于通过基于 DNA 甲基化的机制控制其基因组的哺乳动物和其他真核生物。