Abstract
Pluripotent stem cells are characterized by the capacity to self-renew and to differentiate into all the cell types of the body. To identify novel regulators of pluripotency, we screened cDNA libraries (>30,000 clones) in P19 embryonal carcinoma cells for factors that modulate the expression of a luciferase reporter driven by the promoter of the pluripotency master regulator Nanog. Ninety confirmed hits activated the reporter and 14 confirmed hits inhibited the reporter by more than two-fold. The identified hits were evaluated by gain- and loss-of-functions approaches. The reporter-activating hits Timp2, Hig2, and Mki67ip promoted embryonic stem (ES) cell self-renewal when episomally overexpressed in ES cells, whereas the reporter-inhibiting hits PU.1/Spi1, Prkaca, and Jun induced differentiation of ES cells. Conversely, the knockdown of the activating hits Timp2, Mki67ip, Esrrg, and Dusp7 in ES cells induced differentiation, whereas the knockdown of the reporter-inhibiting hit PU.1/Spi1 led to inhibition of differentiation. One of the novel hits, the RNA-binding protein Mki67ip was further characterized, and found to be overexpressed in ES cells and in early development and downregulated during differentiation. The knockdown o...Continue Reading
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