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Int. J. Mol. Sci. 2018, 19(3), 687; https://doi.org/10.3390/ijms19030687

2A-DUB/Mysm1 Regulates Epidermal Development in Part by Suppressing p53-Mediated Programs

1
Department of Dermatology and Allergic Diseases, University of Ulm, 89081 Ulm, Germany
2
Institute and Out-Patient Clinic of Occupational, Social, and Environmental Medicine, Friedrich-Alexander University, 91054 Erlangen-Nürnberg, Germany
3
Department of Dermatology, University Hospital Heidelberg, 69120 Heidelberg, Germany
4
National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 30 January 2018 / Revised: 18 February 2018 / Accepted: 27 February 2018 / Published: 28 February 2018
(This article belongs to the Special Issue Molecular Research of Epidermal Stem Cells 2017)
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Abstract

Development and homeostasis of the epidermis are governed by a complex network of sequence-specific transcription factors and epigenetic modifiers cooperatively regulating the subtle balance of progenitor cell self-renewal and terminal differentiation. To investigate the role of histone H2A deubiquitinase 2A-DUB/Mysm1 in the skin, we systematically analyzed expression, developmental functions, and potential interactions of this epigenetic regulator using Mysm1-deficient mice and skin-derived epidermal cells. Morphologically, skin of newborn and young adult Mysm1-deficient mice was atrophic with reduced thickness and cellularity of epidermis, dermis, and subcutis, in context with altered barrier function. Skin atrophy correlated with reduced proliferation rates in Mysm1−/− epidermis and hair follicles, and increased apoptosis compared with wild-type controls, along with increases in DNA-damage marker γH2AX. In accordance with diminished α6-Integrinhigh+CD34+ epidermal stem cells, reduced colony formation of Mysm1−/− epidermal progenitors was detectable in vitro. On the molecular level, we identified p53 as potential mediator of the defective Mysm1-deficient epidermal compartment, resulting in increased pro-apoptotic and anti-proliferative gene expression. In Mysm1−/−p53−/− double-deficient mice, significant recovery of skin atrophy was observed. Functional properties of Mysm1−/− developing epidermis were assessed by quantifying the transepidermal water loss. In summary, this investigation uncovers a role for 2A-DUB/Mysm1 in suppression of p53-mediated inhibitory programs during epidermal development. View Full-Text
Keywords: apoptosis; DUB; epidermal barrier; epidermal stem cell; epigenetics; histone modification; Mysm1; p53; p63; skin apoptosis; DUB; epidermal barrier; epidermal stem cell; epigenetics; histone modification; Mysm1; p53; p63; skin
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Wilms, C.; Krikki, I.; Hainzl, A.; Kilo, S.; Alupei, M.; Makrantonaki, E.; Wagner, M.; Kroeger, C.M.; Brinker, T.J.; Gatzka, M. 2A-DUB/Mysm1 Regulates Epidermal Development in Part by Suppressing p53-Mediated Programs. Int. J. Mol. Sci. 2018, 19, 687.

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