Mechanisms of Genomic Imprinting

基因组印记机制

• 批准号: 7256615
• 负责人: Piroska Edit Szabó
• 金额: $ 34.65万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256615
• 关键词: Address; Agreement; Alleles; Beckwith-Wiedemann Syndrome; Binding; Binding Sites; Cells; Chromatin; Chromatin Structure; Condition; DNA; DNA Methylation; Data; Development; Epigenetic Process; Exhibits; Failure; Female; Funding; Gametogenesis; Gene Expression; Genes; Genetic; Genetic Transcription; Genomic Imprinting; Germ Cells; Gonadal structure; Health; Histones; Human; Inherited; Light; Literature; Maintenance; Memory; Methylation; Modification; Mutant Strains Mice; Nephroblastoma; Numbers; Pattern; Protein Binding; Proteins; Recruitment Activity; Research Personnel; Role; Somatic Cell; Testing; Time; base; chromatin immunoprecipitation; human disease; imprint; in vivo; male; mutant; programs; research study

DESCRIPTION (provided by applicant): Imprinted genes exhibit somatic parental specific monoallelic expression. The epigenetic determinants of imprinted gene expression are not fully understood and cannot be solely explained based on CpG methylation-it is not known what mechanism initiates DNA methylation at the imprinting control regions. Chromatin differences at imprinted genes, such as allele-specific \n vivo protein factor binding and/or histone covalent modifications are associated with-and constitute a layer of-cell memory for a number of imprinted genes in somatic cells, but no in vivo evidence exists of such differences or their role at the imprinting control regions in male or female germ-cells. These differences may exist before gonad-specific DNA methylation, and may, therefore, be required for imprint establishment. Such preexisting "primary chromatin differences" in chromatin composition can only be revealed by the analysis of germ cells at the window of time when methylation imprints are attained. Our studies will test the hypothesis, that "primary chromatin differences" between male and female germ cells exist and may be required for DNA methylation imprint establishment at the imprinting control regions. We will analyze the chromatin structure of the H19/lgf2 imprinting control region in normal and mutant somatic cells and also during male and female germ cell development in order to reveal the "primary chromatin difference(s) and confirm the role of these "primary chromatin differences" in imprint establishment. These studies are related to human health in that genomic imprinting underlies a number of human diseases, such as Beckwith-Wiedemann syndrome and Wilm's tumor. Definition of genomic imprinting at a fundamental level should shed further light on the genetic and epigenetic basis of human diseases associated with imprinting failure.

描述（由申请人提供）：印记基因表现出体细胞亲代特异性单等位基因表达。印记基因表达的表观遗传决定因素尚未完全了解，并且不能仅根据 CpG 甲基化进行解释——尚不清楚什么机制在印记控制区域启动 DNA 甲基化。印记基因的染色质差异，例如等位基因特异性体内蛋白质因子结合和/或组蛋白共价修饰，与体细胞中许多印记基因相关并构成细胞记忆层，但没有体内证据表明这种差异或其在雄性或雌性生殖细胞印记控制区域中的作用。这些差异可能在性腺特异性 DNA 甲基化之前就存在，因此可能是印记建立所必需的。这种染色质组成中预先存在的“主要染色质差异”只能通过在获得甲基化印记的时间窗口对生殖细胞进行分析来揭示。我们的研究将检验这一假设，即男性和女性生殖细胞之间存在“主要染色质差异”，并且可能是在印记控制区域建立 DNA 甲基化印记所必需的。我们将分析正常和突变体细胞以及男性和女性生殖细胞发育过程中H19/lgf2印记控制区的染色质结构，以揭示“初级染色质差异”并确认这些“初级染色质差异”在印记建立中的作用。这些研究与人类健康相关，因为基因组印记是许多人类疾病的基础，例如贝克威斯-维德曼综合征和威尔姆氏病 肿瘤。基因组印记的基本定义应进一步阐明与印记失败相关的人类疾病的遗传和表观遗传基础。