Sternness Is Only a State of the Cell

摘要

How the programming and reprogramming of stem/progenitor cells regulate normal cell development and cancer is still notwell known. One of the tools that we have chosen to use to investigate stem cell regulation is the transcriptional repressor ele-ment 1-silencing transcription factor (REST). REST contains a DNA-binding domain and two repressor domains. Once boundto its target genes, REST can interact with several cellular corepressors to regulate epigenetic modifications. REST is expressedin most nonneural cells, including neural stem/progenitor cells (NSCs), but it is absent in most neuronal cells. REST was orig-inally found to be a major transcriptional repressor of neural differentiation. Previously, we found that activation of REST tar-get genes in NSCs was sufficient to cause neuronal differentiation. Furthermore, the activation of REST target genes inmyoblasts was sufficient to override the muscle differentiation pathway and produce a physiologically active neuronal pheno-type. Although REST is normally not expressed in most neural cells, we previously found that approximately 50% of humanmedulloblastomas, a malignant pediatric brain tumor, express REST and that abnormal expression of REST in NSCs causesmedulloblastoma-like cerebellar tumors by blocking neuronal differentiation. Interestingly, REST is also expressed at high lev-els in mouse embryonic stem (mES) cells, but its role in these cells is not understood. Recently, we found that REST maintainsself-renewal and pluripotency in mES cells through suppression of microRNA-2 I (miRNA2 1). Thus, REST is a newly dis-covered element of the interconnected regulatory network that maintains the self-renewal and pluripotency of mES cells. Takentogether, the results of several different studies indicate that stem/progenitor cells are more flexible than previously believedand that a simple alteration of transcriptional regulators in these cells can affect both normal cell development and cancer.