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Acquisition and maintenance of DNA methylation in genomic imprinting

基因组印记中 DNA 甲基化的获取和维持

基本信息

批准号：
8074106
负责人：
Xiajun Li
金额：
$ 31.61万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-17 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8074106
关键词：
Adult Affect Alleles Biological Models Blood Vessels Cancer Etiology Cardiac Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cell Lineage Cell Therapy Cells Co-Immunoprecipitations Complex Congenital Heart Defects Coupled DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases Defect Degenerative Disorder Development Diabetes Mellitus Embryo Embryo Cloning Embryonic Development Embryonic Heart Enzymes Failure Future Gene Targeting Genes Genomic Imprinting Genomics Goals Human Knock-out Lead Life Link Lobular Neoplasia Maintenance Malignant Neoplasms Mammals Mass Spectrum Analysis Mediating Memory Metabolic Diseases Molecular Mus Mutation Nature Neonatal Notch Signaling Pathway Outcomes Research Phenotype Play Pluripotent Stem Cells Process Proteins Publishing RNA Interference Recruitment Activity Role Scaffolding Protein Signal Transduction Somatic Cell Staging Testing Therapeutic Time Vascular System Work Zinc Fingers base embryonic stem cell human ZNF45 protein human disease imprint in utero induced pluripotent stem cell mutant neonatal diabetes mellitus notch protein novel nuclear transfer prevent public health relevance research study stem

项目摘要

DESCRIPTION (provided by applicant): Genomic imprinting is essential for mammalian development. Dysregulation of imprinting genes can lead to cancer, diabetes, cardiovascular diseases and other kinds of human diseases. Although genomic imprinting was identified in mammals almost three decades ago, it is still unclear if genomic imprinting plays a role in late embryonic development. Many unanswered questions persist about the nature of genomic imprinting memory and about how genomic imprints are established and maintained. This proposal aims to uncover the underlying molecular mechanisms of establishment, maintenance and acquisition of DNA methylation imprints in mouse embryos and in cell culture. These objectives can be reached now because we have discovered an important regulator in DNA methylation imprints. Our preliminary results indicate that ZFP57 appears to be required for cardiovascular development. ZFP57 can target DNA methyltransferases to imprinting control regions to initiate and maintain DNA methylation imprints. Our proposed experiments will examine whether ZFP57 regulates LIN-12/Notch signaling in cardiovascular development via its target imprinted gene, thereby linking genomic imprinting to late stages of embryonic development. The expected outcome from this research will further our understanding of the establishment and maintenance of DNA methylation imprints, setting the stage for future studies to unravel the molecular nature of genomic imprinting memory. Successful completion of these experiments will also provide proof of principle for manipulating DNA methylation imprints in pluripotent stem cells for future therapeutic applications. PUBLIC HEALTH RELEVANCE: Dysregulation of genomic imprinting are associated with a variety of human diseases including metabolic diseases, cardiovascular diseases and cancer. Indeed, it was just published that mutations in human Zfp57 result in hypomethylation at multiple imprinted regions and are associated with transient neonatal diabetes and congenital heart defects.

描述（由申请人提供）：基因组印记对于哺乳动物的发育至关重要。印记基因失调可导致癌症、糖尿病、心血管疾病和其他类型的人类疾病。尽管近三十年前在哺乳动物中发现了基因组印记，但仍不清楚基因组印记是否在胚胎发育后期发挥作用。关于基因组印记记忆的本质以及基因组印记如何建立和维持，仍然存在许多悬而未决的问题。该提案旨在揭示小鼠胚胎和细胞培养物中 DNA 甲基化印记建立、维持和获得的潜在分子机制。这些目标现在可以实现，因为我们发现了 DNA 甲基化印记的重要调节因子。我们的初步结果表明 ZFP57 似乎是心血管发育所必需的。 ZFP57 可以将 DNA 甲基转移酶靶向印记控制区域，以启动和维持 DNA 甲基化印记。我们提出的实验将检查 ZFP57 是否通过其目标印记基因调节心血管发育中的 LIN-12/Notch 信号传导，从而将基因组印记与胚胎发育的后期联系起来。这项研究的预期结果将进一步加深我们对 DNA 甲基化印记的建立和维持的理解，为未来研究揭开基因组印记记忆的分子性质奠定基础。这些实验的成功完成还将为未来治疗应用中操纵多能干细胞中的 DNA 甲基化印记提供原理证明。公共卫生相关性：基因组印记失调与多种人类疾病有关，包括代谢疾病、心血管疾病和癌症。事实上，刚刚发表的研究表明，人类 Zfp57 的突变会导致多个印记区域甲基化程度低，并与暂时性新生儿糖尿病和先天性心脏缺陷相关。