Tumor Suppression Group, Spanish National Cancer Research Centre, Madrid, E28029, Spain.
Cell Stem Cell. 2012 Dec 7;11(6):845-52. doi: 10.1016/j.stem.2012.09.014.
The mechanisms responsible for the transcriptional silencing of pluripotency genes in differentiated cells are poorly understood. We have observed that cells lacking the tumor suppressor p27 can be reprogrammed into induced pluripotent stem cells (iPSCs) in the absence of ectopic Sox2. Interestingly, cells and tissues from p27 null mice, including brain, lung, and retina, present an elevated basal expression of Sox2, suggesting that p27 contributes to the repression of Sox2. Furthermore, p27 null iPSCs fail to fully repress Sox2 upon differentiation. Mechanistically, we have found that upon differentiation p27 associates to the SRR2 enhancer of the Sox2 gene together with a p130-E2F4-SIN3A repressive complex. Finally, Sox2 haploinsufficiency genetically rescues some of the phenotypes characteristic of p27 null mice, including gigantism, pituitary hyperplasia, pituitary tumors, and retinal defects. Collectively, these results demonstrate an unprecedented connection between p27 and Sox2 relevant for reprogramming and cancer and for understanding human pathologies associated with p27 germline mutations.
多能性基因在分化细胞中转录沉默的机制尚不清楚。我们观察到，缺乏肿瘤抑制因子 p27 的细胞可以在没有异位 Sox2 的情况下被重新编程为诱导多能干细胞（iPSC）。有趣的是，p27 缺失小鼠的细胞和组织，包括大脑、肺和视网膜，Sox2 的基础表达水平升高，表明 p27 有助于 Sox2 的抑制。此外，p27 缺失的 iPSC 在分化时不能完全抑制 Sox2 的表达。从机制上讲，我们发现分化过程中 p27 与 Sox2 的 SRR2 增强子结合，形成 p130-E2F4-SIN3A 抑制复合物。最后，Sox2 杂合不足在基因水平上挽救了一些 p27 缺失小鼠的特征性表型，包括巨体型、垂体增生、垂体肿瘤和视网膜缺陷。综上所述，这些结果表明 p27 和 Sox2 之间存在一种前所未有的联系，这种联系与重编程和癌症有关，也与理解与 p27 种系突变相关的人类病理有关。
