title: p27(Kip1) directly represses Sox2 during embryonic stem cell differentiation.
abstract: 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.
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Centre, Madrid, E28029, Spain.
authors.forename: Han
authors.initials: H
authors.lastname: Li
authors.forename: Manuel
authors.initials: M
authors.lastname: Collado
authors.forename: Aranzazu
authors.initials: A
authors.lastname: Villasante
authors.forename: Ander
authors.initials: A
authors.lastname: Matheu
authors.forename: Cian J
authors.initials: CJ
authors.lastname: Lynch
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Karine
authors.initials: K
authors.lastname: Rizzoti
authors.forename: Carmen
authors.initials: C
authors.lastname: Carneiro
authors.forename: Gloria
authors.initials: G
authors.lastname: Martínez
authors.forename: Anxo
authors.initials: A
authors.lastname: Vidal
authors.forename: Robin
authors.initials: R
authors.lastname: Lovell-Badge
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000378:metabolism*; D050704:E2F4 Transcription Factor / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D057895:Haploinsufficiency / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D051379:Mice; D010641:Phenotype; D011485:Protein Binding / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D050717:Retinoblastoma-Like Protein p130 / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D050704:E2F4 Transcription Factor; C493763:E2f4 protein, mouse; C493838:Rbl2 protein, mouse; D012097:Repressor Proteins; D050717:Retinoblastoma-Like Protein p130; C099683:SIN3A transcription factor; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D014157:Transcription Factors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D056264:Sin3 Histone Deacetylase and Corepressor Complex