Uncovering the mechanisms underlying maintenance of undifferentiated states in somatic cells and its application for cancer research

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The pluripotency of ES cells is maintained by the coordinated expression of genes in the core regulatory circuitry that includes Oct3/4, Sox2 and Nanog. Rest (also called Nrsf) is abundantly expressed in ES cells and it is a target of the Oct3/4-Sox2-Nanog regulatory network core circuitry. However, the functional significance of Rest in the maintenance of pluripotency in ES cells remains controversial. We herein generated Rest conditional knock-out and REST-inducible ES cell lines. The conditional ablation of Rest showed that Rest is not indispensible for the maintenance of pluripotency, however, it is involved in the suppression of self-renewal genes upon the early differentiation of ES cells. Consistently, the forced expression of REST results in the rapid differentiation of ES cells. Our results indicate that Rest is not necessary for the maintenance of ES cells, while further suggest that the Rest transcriptional repressor is an external factor connecting to the Oct3/4-Sox2-Nanog core regulatory circuitry to induce the early differentiation of ES cells.