Epigenetic Control of Heterochromatin Formation

异染色质形成的表观遗传控制

基本信息

批准号：
7583724
负责人：
RABINDRANATH DE LA FUENTE
金额：
$ 39.75万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7583724
关键词：
Ablation Affect Aneuploidy Animals Binding Biological Cell division Centromere Chromatids Chromosome Pairing Chromosome Segregation Chromosome Structures Chromosomes Complex DNA Methylation DNA Transposable Elements Embryo Environment Epigenetic Process Exhibits Family Female Gene Silencing Genetic Transcription Genome Genome Stability Germ Cells Germ Lines Growth Heterochromatin In Situ Indium Knockout Mice Laboratories Lymphocyte Maintenance Meiosis Meiotic Prophase I Metaphase Methylation Minor Modification Molecular Mus Nuclear Oocytes Oogenesis Pachytene Stage Pattern Ploidies Proteins Research Project Grants Role Staging Tandem Repeat Sequences Testing Transgenic Organisms Translational Regulation X Inactivation base chromatin modification chromatin protein chromatin remodeling demethylation helicase histone modification insight member mouse model preimplantation research study transmission process

项目摘要

Heterochromatin formation is essential for chromosome segregation, epigenetic silencing and X chromosome inactivation. In spite of their biological significance, the mechanisms involved in the establishment of heterochromatin domains during oogenesis are currently unknown. The focus of this proposal will be on two members of the SWIISNF2 family of chromatin remodeling proteins Lsh and A TRX known to have a role in DNA methylation. This proposal is based on the following hypotheses 1) that Lsh is essential for genomic stability during female meiosis; and 2) that both ATRX and Lsh are essential for centromeric heterochromatin formation and epigenetic gene silencing during mouse oocyte growth. The specific objectives include (1) To determine the role of the lymphocyte specific helicase (Lsh) during prophase I of meiosis; (2) To determine whether the Lsh protein has a functional role in centromeric heterochromatin formation during mouse oocyte growth. A transgenic knockout mouse model will be used to determine the mechanisms interfering with homologous chromosome synapsis in Lsh null oocytes during prophase I of meiosis. Particular emphasis will be placed to characterize the molecular interactions between Lsh and ATRX during oogenesis and to determine their functional significance for centromeric heterochromatin formation. These studies will provide critical information regarding the relationship between DNA methylation, heterochromatin formation and epigenetic gene silencing during female meiosis, as well as the mechanisms affecting meiotic centromere function, genomic stability and the molecular mechanisms contributing to the onset of aneuploidy in the mammalian oocyte and pre-implantation embryo.

异染色质形成对于染色体分离，表观遗传沉默和X染色体灭活至关重要。尽管具有生物学意义，但目前尚不清楚在卵子发生过程中涉及异染色质结构域的机制。该提案的重点将放在染色质重塑蛋白LSH的SWIISNF2家族的两个成员上，而TRX已知在DNA甲基化中起作用。该提议基于以下假设1）LSH对于女性减数分裂过程中的基因组稳定性至关重要； 2）在小鼠卵母细胞生长过程中，ATRX和LSH对于丝粒异染色质形成和表观遗传基因沉默至关重要。特定目标包括（1）确定减数分裂预言I期间淋巴细胞特异性解旋酶（LSH）的作用；（2）确定在小鼠卵母细胞生长过程中，LSH蛋白在丝粒异染色质形成中是否具有功能作用。转基因基因敲除小鼠模型将用于确定在减数分裂的预言I期间LSH无效卵母细胞中同源染色体突触的机制。将特别重点以表征卵子发生过程中LSH和ATRX之间的分子相互作用，并确定其对丝粒异染色质形成的功能意义。这些研究将提供有关女性减数分裂过程中DNA甲基化，异质染色质形成和表观遗传基因沉默之间关系的关键信息，以及影响减数分裂中心粒功能，基因组稳定性和分子机制的机制，有助于有助于哺乳动物型和型号的卵巢型emocyplantation emcyplantation和分子机制。