Genetics of DNA methylation patterning of arabidopsis.

拟南芥 DNA 甲基化模式的遗传学。

基本信息

批准号：
9196358
负责人：
STEVEN E JACOBSEN
金额：
$ 30.8万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9196358
关键词：
Arabidopsis Binding Biological Assay Cancer Biology Cancer Etiology Chemicals Chromosomes Collaborations Cytosine DNA DNA Methylation DNA Modification Methylases DNA Sequence DNA-Binding Proteins Defect Epigenetic Process Eukaryota Gene Expression Regulation Gene Silencing Genes Genetic Genetic Screening Genomics Grant Hereditary, Type III, Motor and Sensory Neuropathy Histone H3 Homologous Gene Hypermethylation Individual Instruction Laboratories Lead Light Maintenance Mammals Methods Methylation Methyltransferase Modification Molecular Genetics Pathway interactions Plant Model Play Process Proteins RNA Recruitment Activity Regulator Genes Research Role Series Site Small Interfering RNA System Techniques Tissues Tumor Suppressor Genes Work X Inactivation demethylation experimental study gene function genome-wide histone methylation histone methyltransferase imprint methylation pattern mutant prevent reverse genetics structural biology tumor

项目摘要

Cytosine DNA methylation is an epigenetic mark for gene silencing that is important in many gene regulatory systems including mammalian imprinting, X-chromosome inactivation, and the silencing of transposons and other DNA sequences containing either direct or inverted repeats. Methylation is important in cancer biology, as tumors often show both genome wide demethylation and hypermethylation of specific tumor suppressor genes. We are studying the mechanisms of DNA methylation control in the model plant Arabldopsis, which has methylation systems that have much in common with mammalian systems. In Arabldopsis, the initial establishment of methylation (de novo methylation) requires the activity of DRM2, a homolog of mammalian DnmtS, which is guided to appropriate targets, at least in part, by small interfering RNAs. Once established, DNA methylation is maintained by three different systems for methylation of cytosines in three different sequence contexts, CG, CHG and CHH (asymmetric). CG methylation is maintained by MET1, a homolog of mammalian Dnmtl CHG methylation is maintained by the CMT3 DNA methyltransferase, which is guided to appropriate targets by the methylation of histone H3. CHH methylation is maintained by the persistent activity of DRM2, which is targeted by small interfering RNAs. In this proposal, we plan to further study these DNA methylation control mechanisms. Genetic screens are being used to identify genes required for proper de novo DNA methylation, and we plan to perform a detailed molecular genetic characterization of these genes to understand more about the mechanism by which they contribute to de novo methylation. We have also begun using structural biology, in collaboration with Dinshaw Patel's laboratory, to help in our understanding of individual components of the de novo DNA methylation pathway. We are also applying genomics techniques the study of RNA-directed DNA methylation in order to assist in our understanding the genome wide functions of DNA methylation. These studies should shed new light on DNA methylation systems in Arabldopsis and have implications for related systems in mammals and other eukaryotes.

胞嘧啶 DNA 甲基化是基因沉默的表观遗传标记，在许多基因调控中非常重要系统包括哺乳动物印记、X染色体失活和转座子沉默其他含有直接或反向重复序列的 DNA 序列。甲基化在癌症中很重要生物学，因为肿瘤通常表现出特定肿瘤的全基因组去甲基化和高甲基化抑制基因。我们正在研究模型植物中DNA甲基化控制的机制拟南芥的甲基化系统与哺乳动物系统有很多共同点。在拟南芥中，甲基化的初步建立（从头甲基化）需要DRM2的活性，DRM2是一种哺乳动物 DnmtS 的同源物，至少部分地通过小干扰引导至适当的目标 RNA。一旦建立，DNA 甲基化由三个不同的系统维持三种不同序列背景下的胞嘧啶：CG、CHG 和 CHH（不对称）。 CG甲基化是由 MET1 维持，哺乳动物 Dnmtl 的同源物 CHG 甲基化由 CMT3 DNA 维持甲基转移酶，通过组蛋白 H3 的甲基化引导至适当的靶标。 CHH甲基化是由 DRM2 的持续活性维持的，DRM2 是小干扰 RNA 的靶标。在这个根据建议，我们计划进一步研究这些DNA甲基化控制机制。基因筛查正在进行中用于识别正确的从头 DNA 甲基化所需的基因，我们计划进行详细的研究这些基因的分子遗传学特征，以更多地了解它们的机制有助于从头甲基化。我们还开始与以下机构合作使用结构生物学丁肖·帕特尔 (Dinshaw Patel) 的实验室，帮助我们了解 DNA 的各个组成部分甲基化途径。我们还应用基因组学技术来研究 RNA 导向的 DNA 甲基化，以帮助我们了解 DNA 甲基化的全基因组功能。这些研究应该为拟南芥中的 DNA 甲基化系统提供新的线索，并对相关的研究产生影响。哺乳动物和其他真核生物中的系统。