Non-random chromosome segregation in mouse embryonic stem cells

小鼠胚胎干细胞中的非随机染色体分离

• 批准号: 7590380
• 负责人: Daniel J Burke
• 金额: $ 16.86万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590380
• 关键词: Adopted; Age; Behavior; Cancerous; Cells; Chromatids; Chromosome Segregation; Chromosomes; Chromosomes, Human, Pair 7; Coupled; DNA; DNA biosynthesis; Data; Dynein ATPase; Epigenetic Process; Fluorescent in Situ Hybridization; Genetic; Goals; Homologous Gene; Inherited; Instruction; Kinetochores; Lead; Mitosis; Modeling; Molecular; Molecular Motors; Mus; Pattern; Process; Public Health; Recording of previous events; Research; Role; Sister; Sister Chromatid; Stem cells; Testing; Time; Upper arm; base; cell type; embryonic stem cell; imprint; prevent; research study; segregation; self-renewal

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the molecular mechanism of non-random chromatid segregation in mouse embryonic stem cells. The immortal strand hypothesis - posits that stem cells segregate the "oldest" DNA strands of all chromosomes asymmetrically to the self-renewing stem cells as a mechanism to prevent the stem cell from inheriting any errors in DNA replication that could lead to a cancerous state. Stem cells use this strategy on a chromosome by chromosome basis to direct the segregation of specific chromatids. Specifically, mouse embryonic stem cells selectively segregate chromatids of chromosome 7 and we propose to determine the mechanism. This proposal has two Aims. The first Aim is to test the hypothesis that non-random chromatid segregation depends on the replicative age of the DNA using chromosome oriented fluorescence in situ hybridization (CO-FISH). The second aim will test the hypothesis that LRD, a homolog of outer-arm 2-axonemal dynein heavy chain, functions as a molecular motor to direct non-random chromatid segregation. PUBLIC HEALTH REVELANCE: Stem cells are unique in having the ability to "self renew" and at the same time to be capable of differentiating into every cell in the body. It is critical that stem cells have mechanisms that protect their genetic integrity so that they may maintain their stem cell identity while faithfully executing the instructions needed to adopt many different cellular fates. One mechanism that stem cells use is to selectively segregate chromosomes after they are replicated so that specific copies are kept together. This is a mysterious process since we generally believe that replicated chromosomes are segregated randomly. Clearly, stem cells are different in this regard. The goal of this research is to understand the mechanism of selective chromosome segregation in stem cells.

描述（申请人提供）：本研究的长期目标是了解小鼠胚胎干细胞中非随机染色单体分离的分子机制。永生链假说——假设干细胞将所有染色体的“最古老”DNA链与自我更新干细胞不对称地分离，作为防止干细胞遗传DNA复制中任何可能导致癌症状态的错误的机制。干细胞在逐条染色体的基础上使用这种策略来指导特定染色单体的分离。具体来说，小鼠胚胎干细胞选择性地分离 7 号染色体的染色单体，我们建议确定其机制。该提案有两个目标。第一个目的是使用染色体定向荧光原位杂交 (CO-FISH) 来检验非随机染色单体分离取决于 DNA 复制年龄的假设。第二个目标将检验以下假设：LRD（外臂 2-轴丝动力蛋白重链的同源物）作为分子马达来指导非随机染色单体分离。 公众健康启示：干细胞具有独特的“自我更新”能力，同时能够分化为体内的每个细胞。至关重要的是，干细胞具有保护其遗传完整性的机制，以便它们可以保持其干细胞身份，同时忠实地执行采取许多不同细胞命运所需的指令。干细胞使用的一种机制是在复制后选择性地分离染色体，以便将特定的副本保留在一起。这是一个神秘的过程，因为我们通常认为复制的染色体是随机分离的。显然，干细胞在这方面是不同的。这项研究的目的是了解干细胞中选择性染色体分离的机制。