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

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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.