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Discovering the basis of the essential function of DNMT1 in wasp embryogenesis

发现 DNMT1 在黄蜂胚胎发生中的基本功能基础

基本信息

批准号：
9087781
负责人：
Jeremy Lynch
金额：
$ 7.84万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9087781
关键词：
Address Affect Animals Basic Cancer Research Biological Biological Models Blastoderm Caenorhabditis elegans Catalytic Domain Cell Lineage Complement Complex Cytosine DNA Methylation DNA Modification Methylases Defect Development Disease Double-Stranded RNA Drosophila genus Embryo Embryonic Development Enzymes Epigenetic Process Eukaryota Failure Gene Expression Gene Expression Regulation Generations Genes Genetic Genome Genomic DNA Health Homologous Gene Human Invertebrates Knowledge Maintenance Malignant Neoplasms Medical Messenger RNA Methylation Methyltransferase Modeling Modification Organism Pattern Play Process RNA Interference Regulation Repression Research Role Sampling Site Staging System Time Tissues Transfer RNA Ursidae Family Vertebrates Wasps Work base bisulfite sequencing cell behavior fly gastrulation genome sequencing human disease insight knock-down mRNA Expression methylation pattern paralogous gene prevent public health relevance tool transcriptome transcriptome sequencing whole genome

项目摘要

DESCRIPTION (provided by applicant): DNA methylation plays a crucial role in regulating genome function in a wide variety of biological contexts in humans and other eukaryotes. In humans, aberrations of methylation are implicated in many diseases, including cancers. Surprisingly, most of the cellular machinery required for methylation has been lost in the main invertebrate model systems, the worm C. elegans and the fly Drosophila. Thus, the powerful genetic tools available in those systems have not been brought to bear on the questions of the fundamental roles for DNA methylation in development and disease. The wasp Nasonia has many of the advantages of the invertebrate model systems (e.g., small, sequenced and annotated genome, fast development, powerful genetic tools). It possesses the full complement of eukaryotic DNA methyltransferases (DNMT1, 2, and 3), and the genome has significant levels of methylation at typical CpG sites. There are three DNMT1 paralogs (a, b, and c) in Nasonia. When DNMT1a is knocked down by RNAi, embryonic lethality results. This project aims to answer four questions about the roles of DNA methylation and DNMT1a. 1) Is DNA methylation dynamic in early wasp embryogenesis? 2) Do the patterns of methylation in the early embryo depend on DNMT1a function? 3) How does the loss of DNMT1a affect the expression of genes during early embryogenesis? 4) Are the genes whose methylation state is dependent on DNMT1a correlated with those whose mRNA expression levels change after DNMT1a RNAi? Questions 1 and 2 will be addressed with Whole Genome Bisulfite Sequence, and Question 3 will use an RNA-sequencing approach, and Question 4 will use a computational approach. Medical Relevance: The Nasonia embryo provides a simple, accessible and powerful model system to gain basic insights into the functions of DNMT1 enzymes and DNA methylation, topics that are of great relevance to human health. Of the main types of methylation found in eukaryotes, Nasonia appears to employ almost exclusively gene body methylation, which is increasingly recognized as a major aspect of the disease relevance of DNA methylation. Thus Nasonia presents a special opportunity to study the importance of gene body methylation in isolation from potential confounding effects of other modes of DNA methylation.