MOZ-Mediated Repression of p16INK4a Is Critical for the Self-Renewal of Neural and Hematopoietic Stem Cells

Authors

  • Flor M. Perez-Campo,

    Corresponding author
    1. Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom
    • Correspondence: Flor M. Perez-Campo, Ph.D., Department of Internal Medicine, Hospital U. M. Valdecilla-IFIMAV, University of Cantabria, Av., Marques de Valdecilla, s/n, 39008, Santander, Spain; e-mail: f.perezcampo@unican.es; or Georges Lacaud, Ph.D., Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road M20 4BX, UK. Telephone: 44-161-446-8380; Fax: 44-161-446-3109; e-mail: georges.lacaud@cruk.manchester.ac.uk

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  • Guilherme Costa,

    1. Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom
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  • Michael Lie-a-Ling,

    1. Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom
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  • Stefano Stifani,

    1. Montreal Neurological Institute, Montreal, Quebec, Canada
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  • Valerie Kouskoff,

    1. Cancer Research UK Stem Cell Haematopoiesis Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom
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  • Georges Lacaud

    Corresponding author
    1. Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom
    • Correspondence: Flor M. Perez-Campo, Ph.D., Department of Internal Medicine, Hospital U. M. Valdecilla-IFIMAV, University of Cantabria, Av., Marques de Valdecilla, s/n, 39008, Santander, Spain; e-mail: f.perezcampo@unican.es; or Georges Lacaud, Ph.D., Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road M20 4BX, UK. Telephone: 44-161-446-8380; Fax: 44-161-446-3109; e-mail: georges.lacaud@cruk.manchester.ac.uk

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Abstract

Although inhibition of p16INK4a expression is critical to preserve the proliferative capacity of stem cells, the molecular mechanisms responsible for silencing p16INK4a 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 p16INK4a. In the absence of the HAT activity of MOZ, expression of p16INK4a is upregulated in progenitor and stem cells, inducing an early entrance into replicative senescence. Genetic deletion of p16INK4a reverses the proliferative defect in both MozHAT/ hematopoietic and neural progenitors. Our results suggest a critical requirement for MOZ HAT activity to silence p16INK4a expression and to protect stem cells from early entrance into replicative senescence. Stem Cells 2014;32:1591–1601

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