Genetics of DNA methylation patterning of arabidopsis.

拟南芥 DNA 甲基化模式的遗传学。

• 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
• 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

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学标志，在许多基因调控中起重要作用 包括哺乳动物印记、X染色体失活和转座子沉默以及 包含正向或反向重复序列的其他DNA序列。甲基化在癌症中很重要 生物学，因为肿瘤通常表现为基因组范围的去甲基化和特定肿瘤的高甲基化 抑制基因。我们正在研究模式植物中DNA甲基化控制的机制 失智症，它的甲基化系统与哺乳动物系统有许多共同之处。在……里面 失智症，甲基化的初始建立(从头甲基化)需要DRM2的活性，a 哺乳动物DNMT的同源基因，至少部分通过小干扰引导到适当的靶点 RNA。一旦确定，DNA甲基化由三种不同的甲基化系统维持 胞嘧啶在三种不同的序列环境中，CG，CHG和CHH(不对称)。CG甲基化是 由MET1维持的哺乳动物Dnmtl CHG甲基化的同源基因由CMT3 DNA维持 甲基转移酶，它被组蛋白H3的甲基化引导到适当的靶点。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 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 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 这些基因的分子遗传学特征，以更多地了解它们 有助于从头开始甲基化。我们还开始使用结构生物学，与 Dinshaw Patel的实验室，帮助我们了解从头DNA的各个组成部分 甲基化途径。我们也在应用基因组学技术来研究RNA引导的DNA 以帮助我们理解DNA甲基化在全基因组范围内的功能。这些 研究应该为失明紫质的DNA甲基化系统提供新的线索，并对相关研究产生影响 哺乳动物和其他真核生物的系统。