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

ES细胞的多能性是通过基因在包括Oct3/4、Sox2和Nanog在内的核心调控电路中的协调表达来维持的。REST(也称为Nrsf)在ES细胞中大量表达，是Oct3/4-Sox2-Nanog调控网络核心电路的靶点。然而，REST在维持ES细胞多能性中的功能意义仍然存在争议。在此，我们建立了REST条件基因敲除和REST诱导的ES细胞系。REST的条件性消融表明，REST不是维持多能性所必需的，但它参与了抑制ES细胞早期分化的自我更新基因。一贯地，REST的强制表达导致ES细胞的快速分化。我们的结果表明，REST不是维持ES细胞所必需的，同时进一步表明REST转录抑制因子是一个外部因素，连接到Oct3/4-Sox2-Nanog核心调控电路，诱导ES细胞的早期分化。

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.