p27Kip1 Directly Represses Sox2 during Embryonic Stem Cell Differentiation

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. [Display omitted] ► Loss of the tumor suppressor p27 upregulates the pluripotency gene Sox2 ► Absence of p27 allows reprogramming without ectopic Sox2 ► p27 associates with a Sox2 enhancer together with a repressive complex ► SOX2 mediates some of the main phenotypic defects of p27 null mice The tumor suppressor p27Kip1 has an unexpected role in direct transcriptional regulation of Sox2 during the differentiation of pluripotent cells.