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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：
8645643
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 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8645643
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 DNA Genomic Imprinting 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 transcriptional intermediary factor 1

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.

描述（由申请人提供）：基因组印记对哺乳动物发育至关重要。印迹基因的失调可导致癌症、糖尿病、心血管疾病等多种人类疾病。尽管基因组印记在近三十年前就在哺乳动物中被发现，但基因组印记是否在晚期胚胎发育中起作用仍不清楚。关于基因组印记记忆的性质以及基因组印记是如何建立和维持的，仍然存在许多未解之谜。本研究旨在揭示小鼠胚胎和细胞培养中DNA甲基化印记的建立、维持和获得的分子机制。这些目标现在可以实现，因为我们已经发现了DNA甲基化印记的重要调节因子。我们的初步结果表明，ZFP 57似乎是心血管发育所必需的。ZFP 57可以将DNA甲基转移酶靶向到印迹控制区域，以启动和维持DNA甲基化印迹。我们提出的实验将研究ZFP 57是否通过其靶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晚期阶段联系起来。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本质奠定基础。这些实验的成功完成也将为将来的治疗应用提供操纵多能干细胞中DNA甲基化印记的原理证明。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genomic imprinting defect in Zfp57 mutant iPS cell lines.

DOI：
10.1016/j.scr.2016.01.018
发表时间：
2016-03
期刊：
Stem cell research
影响因子：
1.2
作者：
McDonald CM;Liu L;Xiao L;Schaniel C;Li X
通讯作者：
Li X

Zfp57 mutant ES cell lines directly derived from blastocysts.

DOI：
10.1016/j.scr.2015.12.038
发表时间：
2016-03
期刊：
Stem cell research
影响因子：
1.2
作者：
Lau HT;Liu L;Li X
通讯作者：
Li X

Differential regulation of genomic imprinting by TET proteins in embryonic stem cells.

DOI：
10.1016/j.scr.2015.08.010
发表时间：
2015-09
期刊：
Stem cell research
影响因子：
1.2
作者：
Liu L;Mao SQ;Ray C;Zhang Y;Bell FT;Ng SF;Xu GL;Li X
通讯作者：
Li X

Genomic imprinting is variably lost during reprogramming of mouse iPS cells.

DOI：
10.1016/j.scr.2013.05.011
发表时间：
2013-09
期刊：
STEM CELL RESEARCH
影响因子：
1.2
作者：
Takikawa, Sachiko;Ray, Chelsea;Wang, Xin;Shamis, Yulia;Wu, Tien-Yuan;Li, Xiajun
通讯作者：
Li, Xiajun