In our earlier work, we compared the global expression profiles of mouse ES cells and trophoblast stem (TS) cells by DNA microarrays. We studied Esg1, one of the genes identified as a gene expressed specifically in ES cells, and found that the gene encodes an RNA-binding protein that binds to many RNA targets. We have also compared the expression profiles of mouse ES cells undergoing neural differentiation in vitro and those of adult neural stem progenitor (NS) cells. The results suggested that ES cells undergoing neural differentiation in vitro recapitulate the development of neural lineages in vivo. We also inferred a set of 4,000 genes, the expression of which increased with neural commitment differentiation;it can be used as a scale for the degree of commitment to neural differentiation. We also carried out global gene expression profiling of mouse embryonic germ (EG) cells and multipotent adult stem cells (MAPCs). We have carried out high-throughput in situ hybridization assays on ES cell cultures for 244 genes. We found that three genes (Zscan4, Whsc2, and Rhox9) showed a spotty expression pattern (spot-in-colony pattern). We also found nine genes that showed a relatively heterogeneous expression pattern (mosaic-in-colony pattern: Zfp42/Rex1, Rest, Atf4, Pa2g4, E2f2, Nanog, Dppa3/Pgc7/Stella, Esrrb, and Fscn1). This indicates the presence of a heterogeneous cell population in undifferentiated ES cell cultures. As the baseline information to understand the gene expression regulation in ES cells, we have measured the mRNA half-life of essentially all mouse genes by using DNA microarrays. Recently, we have also demonstrated that principal component analysis of global gene expression profiles map cells in multidimensional transcript profile space and the positions of differentiating cells progress in a stepwise manner along trajectories starting from undifferentiated embryonic stem (ES) cells located in the apex. We have presented three 'cell lineage trajectories', which represent the differentiation of ES cells into the first three lineages in mammalian development: primitive endoderm, trophoblast and primitive ectoderm/neural ectoderm. The positions of the cells along these trajectories seem to reflect the developmental potency of cells and can be used as a scale for the potential of cells. Indeed, we have shown that embryonic germ cells and induced pluripotent (iPS) cells are mapped near the origin of the trajectories, whereas mouse embryo fibroblast and fibroblast cell lines are mapped near the far end of the trajectories. We studied the molecular processes that are associated with these cell lineage trajectories by microarray-based gene expression profiling of the fibroblast cells being converted to the iPS cells. We found that many early embryonic genes are reactivated during the early phase of iPS cell formation from mouse fibroblast cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000662-12
Application #
8552434
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2012
Total Cost
$842,269
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
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