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）：印迹基因表现出躯体父母特异性单相表达。印迹基因表达的表观遗传决定因素尚未完全理解，不能完全根据CpG甲基化来解释，它不知道是什么机制在印记控制区域引发了DNA甲基化。印刷基因的染色质差异，例如同类特异性\ n Vivo蛋白因子的结合和/或组蛋白共价修饰与/或组蛋白共价修饰有关，并且构成了体体细胞中许多刻度印迹基因的细胞记忆，但没有体内证据或它们在男性或女性或女性或女性或女性或女性或女性或女性或女性中存在的差异证据。这些差异可能存在于性腺特异性DNA甲基化之前，因此可能需要建立印记。这种早期存在的“原代染色质差异”只能通过在获得甲基化烙印的时间窗口的分析来揭示出染色质组成。我们的研究将检验以下假设，即男性和雌性生殖细胞之间存在“原发性染色质差异”，并且可能需要在印记控制区域DNA甲基化烙印建立所必需的。我们将分析正常和突变体细胞中H19/LGF2烙印区域的染色质结构，以及在男性和女性生殖细胞发育期间，以揭示“原发性染色质差异（S）并确认这些“原发性染色质差异”在现象中的作用。肿瘤的基因组印记的定义应进一步阐明与烙印失败相关的人类疾病的遗传和表观遗传基础。