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DNA Methylation in Drosophila

果蝇 DNA 甲基化

基本信息

批准号：
7747924
负责人：
KEITH A MAGGERT
金额：
$ 26.13万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7747924
关键词：
Address Adopted Adult Affect Area Behavior Behavioral Genetics Biological Assay Cell Maintenance Cell division Cells Chromatin Structure Chromosomes Congenital Abnormality Cytosine DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases DNA Sequence Data Development Discrimination Disease Drosophila genus Embryo Exhibits Female Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genome Genomic Imprinting Genotype Goals Hereditary Disease Human Immunofluorescence Immunologic In Situ Hybridization Individual Inherited Investigation Life Link Location Malignant Neoplasms Mammals Maps Mediating Memory Methylation Mitotic Modeling Molecular Monitor Mutate Mutation Nature Organism Parents Phenotype Plants Proteins RNA Reagent Recombinant DNA Regulation Reporter Genes Research Research Personnel Role Sex Chromosomes Somatic Cell Specificity Stem cells Techniques Testing Time Tissues Transgenes Ursidae Family Work X Chromosome Y Chromosome autosome base bisulfite chromosome loss genetic analysis homologous recombination imprint male maternal imprint mutant next generation novel offspring paternal imprint positional cloning programs sex sex-specific imprints sperm cell study characteristics

项目摘要

Genomic imprinting is a reversible and differential mark on a set of chromosomes that is determined by the sex of the transmitting parent. This imprint may dramatically affect chromosome behavior or gene expression, and disruption of a proper imprint may result in chromosome loss, cancer, birth defects, or genetic disease. An individual has both maternal and paternal imprints, reflecting that half of its genome has been inherited from each parent. Both sets of imprints are stably maintained throughout the life of an organism. In some cells (e.g., human sperm stem cells), this maintenance may last through thousands of cell divisions over the course of a century. As each chromosome is transmitted to the next generation, all parental imprints are erased in favor of a new set of imprints appropriate to the sex of the transmitting individual. However, since the imprints are maintained, established, and interpreted through unknown mechanisms, it is not known how loss of imprinting leads to disease. Our long-term goal is to understand how sex-specific imprints are established by both males and females, and maintained by the offspring, resulting in parent-of-origin-specific genetic behaviors. Our specific hypothesis is that DNA methylation is an important but transient feature of genomic imprinting. We base this hypothesis on analysis of genomic imprints in fruit flies mutant for the sole known DNA methyltransferase, Mt2. Our preliminary data suggest that DNA methylation is required maternally for establishment of paternal imprints, indicating that the paternal imprint is controlled by the maternal genotype. Based on these observations, we propose to focus our research on imprint establishment by pursuing three specific aims: 1. Identify the DNA sequence that is targeted for methylation by Mt2. We will identify which sequences become methylated by introducing an imprintable transgene, active throughout development and post-mitotic adulthood, and monitoring DNA methylation levels and chromatin structure as they correlate with gene activity. 2. Determine the mode of specificity of Mt2activity for paternally-derived chromosomes. Thekey feature of genomic imprinting is the discrimination of paternal from maternal chromosomes, without regard to chromosome sequence. We will focus on testing possible models of chromosome discrimination, including localized gene activity and differences in chromatin structure of maternal and paternal genomes. 3. Identify genetic factors responsible for establishing genomic imprints. We have identified a genetic interval containing a gene required for the establishment of a maternal imprint. We will identify which gene is involved in maternal imprint establishment, and begin to investigate its mode of action.

基因组印记是一组染色体上的可逆和差异标记，其由基因组印记决定。传播父母的性别。这种印记可能会显著影响染色体行为或基因表达，并且适当印记的破坏可能导致染色体丢失、癌症、出生缺陷或遗传疾病。一个个体具有母亲和父亲的印记，反映出其基因组的一半是遗传自每一位家长。这两组印记在生物体的整个生命过程中稳定地维持。在一些细胞中（例如，人类精子干细胞），这种维持可能会持续数千次细胞分裂的过程中，世纪。当每条染色体传递给下一代时，所有的父母印记都会被擦除，一套新的印记适合于传播个体的性别。然而，由于这些印记是维持，建立，并通过未知的机制解释，它是不知道如何失去印记导致疾病。我们的长期目标是了解男性和女性如何建立性别特异性印记，并由后代维持，从而导致特定于亲本的遗传行为。我们的假设是 DNA甲基化是基因组印记的重要但短暂的特征。我们将这个假设建立在果蝇突变体中唯一已知的DNA甲基转移酶Mt2的基因组印记分析。我们初步数据表明DNA甲基化是建立父系印记所必需的，表明父系印记受母系基因型控制。根据这些观察，我们我建议把我们的研究重点放在建立印记上，追求三个具体目标： 1.鉴定Mt2甲基化靶向的DNA序列。我们会找出哪些序列通过引入可压印的转基因而甲基化，在整个发育和有丝分裂后都有活性成年期，并监测DNA甲基化水平和染色质结构，因为它们与基因活性相关。 2.确定Mt2活性对父系来源染色体的特异性模式。Thekey 基因组印记的一个特征是区分父系和母系染色体，而不考虑染色体序列我们将集中测试可能的染色体辨别模型，包括本地化的基因活性和母亲和父亲基因组的染色质结构的差异。 3.确定负责建立基因组印记的遗传因素。我们发现了一种基因包含建立母体印记所需的基因的间隔。我们将确定哪个基因参与母体印记的建立，并开始研究其作用方式。