Understanding molecular mechanism and biological siginificance of dynamic fluctuation and heterogeneity of gene expression in ES cells and in the early mouse embryo

了解ES细胞和早期小鼠胚胎基因表达动态波动和异质性的分子机制和生物学意义

• 批准号: 158972463
• 负责人: Dr. Takashi Hiiragi
• 金额: --
• 依托单位: Hubrecht Institute
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/158972463?language=en
• 关键词: Understanding; molecular; mechanism; biological; siginificance

For the progress in stem cell research, it is essential to understand the molecular nature of pluripotency in embryonic stem (ES) cells. While pluripotency has been assumed to be a “static” status of a particular cell type, with ES cells being a homogeneous population, recent findings in mouse ES cells and early embryos suggest that it may in fact represent a certain condition of dynamic equilibrium of heterogeneous populations. In undifferentiated ES cells, a number of subpopulations are identified in terms of expression of pluripotency genes. Consistently, mouse embryonic cells that develop to form the pluripotent inner cell mass (ICM) in blastocyst, exhibit highly heterogeneous, and presumably stochastic, expression pattern for the lineage markers.The primary aim of this project is to understand the unique principle underlying maintenance of the pluripotent ES cells and formation of the ICM in the mouse embryo. In particular, dynamic spatiotemporal change in gene expression will be fully characterized by 4D live-imaging ES cell culture and mouse embryonic development. We will focus on Nanog and Stella genes, and investigate the role of epigenetic markings in the regulation of gene expression variation. Biological significance of the dynamic heterogeneity will be explored in ES cells and in mouse embryos by manipulating the molecular components and epigenetic markings under equilibrium. An attractive hypothesis is that this dynamic nature may be an essential feature of pluripotency and interaction of distinct subpopulations may be required for propagation of the pluripotent status. Full understanding of the dynamic equilibrium at molecular and systems level will provide insight into pluripotency maintenance in ES cells.

了解胚胎干细胞（ES细胞）多能性的分子本质对于干细胞研究的进展至关重要。虽然多能性被认为是一种特定细胞类型的“静态”状态，ES细胞是一个同质群体，但最近在小鼠ES细胞和早期胚胎中的发现表明，它实际上可能代表了异质群体动态平衡的某种条件。在未分化的ES细胞中，根据多能性基因的表达鉴定了许多亚群。然而，小鼠胚胎细胞在胚泡中发育形成多能性内细胞团（ICM），其谱系标记物的表达模式具有高度异质性和随机性，本项目的主要目的是了解小鼠胚胎多能性ES细胞维持和ICM形成的独特原理。特别是，基因表达的动态时空变化将通过4D活体成像ES细胞培养和小鼠胚胎发育来充分表征。我们将专注于Nanog和Stella基因，并研究表观遗传标记在基因表达变异调控中的作用。动态异质性的生物学意义，将探讨在ES细胞和小鼠胚胎的分子成分和平衡下的表观遗传标记。一个有吸引力的假设是，这种动态性质可能是多能性的一个基本特征，并且多能状态的传播可能需要不同亚群的相互作用。从分子水平和系统水平对动态平衡的充分理解将有助于深入了解ES细胞的多能性维持。