title: MOZ-mediated repression of p16(INK) (4) (a) is critical for the self-renewal of neural and hematopoietic stem cells.
abstract: Although inhibition of p16(INK4a) expression is critical to preserve the proliferative capacity of stem cells, the molecular mechanisms responsible for silencing p16(INK4a) expression remain poorly characterized. Here, we show that the histone acetyltransferase (HAT) monocytic leukemia zinc finger protein (MOZ) controls the proliferation of both hematopoietic and neural stem cells by modulating the transcriptional repression of p16(INK4a) . In the absence of the HAT activity of MOZ, expression of p16(INK4a) is upregulated in progenitor and stem cells, inducing an early entrance into replicative senescence. Genetic deletion of p16(INK4a) reverses the proliferative defect in both Moz(HAT) (-) (/) (-) hematopoietic and neural progenitors. Our results suggest a critical requirement for MOZ HAT activity to silence p16(INK4a) expression and to protect stem cells from early entrance into replicative senescence.
authors.affiliation: Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom.
authors.forename: Flor M
authors.initials: FM
authors.lastname: Perez-Campo
authors.forename: Guilherme
authors.initials: G
authors.lastname: Costa
authors.forename: Michael
authors.initials: M
authors.lastname: Lie-A-Ling
authors.forename: Stefano
authors.initials: S
authors.lastname: Stifani
authors.forename: Valerie
authors.initials: V
authors.lastname: Kouskoff
authors.forename: Georges
authors.initials: G
authors.lastname: Lacaud
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D002469:Cell Separation; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D020868:Gene Silencing; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D013687:Telencephalon / Q000166:cytology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D018952:Antigens, CD34; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051548:Histone Acetyltransferases; C511438:MOZ protein, mouse; D019009:Proto-Oncogene Proteins c-kit
keywords: Epigenetics; Hematopoietic stem cell; Histone acetylation; MOZ; Neural stem cells; Senescence