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

Christina Wilms1, Ioanna Krikki2, Adelheid Hainzl3

  • 1Department of Dermatology and Allergic Diseases, University of Ulm, 89081 Ulm, Germany. christinawilms@gmx.net.

International Journal of Molecular Sciences
|March 3, 2018
PubMed

Insights

The histone H2A deubiquitinase 2A-DUB/Mysm1 is crucial for skin development. Its absence leads to skin atrophy by promoting p53-mediated inhibition, which can be reversed by removing p53.

Area of Science:

  • Dermatology and Epigenetics
  • Molecular Biology
  • Developmental Biology

Background:

  • Epidermal development relies on transcription factors and epigenetic modifiers.
  • Histone H2A deubiquitinase 2A-DUB/Mysm1 is an epigenetic regulator.
  • Its role in skin homeostasis is not well understood.

Purpose of the Study:

  • To investigate the function of 2A-DUB/Mysm1 in skin development and homeostasis.
  • To analyze the effects of Mysm1 deficiency on epidermal structure and function.
  • To identify molecular mechanisms underlying Mysm1's role in the epidermis.

Main Methods:

  • Systematic analysis of Mysm1-deficient mice and skin-derived epidermal cells.
  • Morphological and histological examination of skin.
  • Assessment of cell proliferation, apoptosis, and DNA damage (γH2AX).
  • In vitro colony formation assays for epidermal progenitors.
  • Molecular analysis to identify interacting proteins and pathways.
  • Generation and analysis of Mysm1-/-p53-/- double-deficient mice.

Main Results:

  • Mysm1-deficient mice exhibited atrophic skin with reduced thickness and cellularity.
  • Decreased epidermal and hair follicle proliferation, increased apoptosis, and elevated γH2AX levels were observed.
  • Reduced numbers of epidermal stem cells (α6-Integrinhigh+CD34+) and impaired progenitor colony formation in vitro.
  • p53 was identified as a key mediator, driving pro-apoptotic and anti-proliferative gene expression.
  • Complementation of Mysm1 deficiency with p53 deficiency rescued skin atrophy.

Conclusions:

  • 2A-DUB/Mysm1 plays a critical role in suppressing p53-mediated inhibitory programs during epidermal development.
  • Mysm1 is essential for maintaining epidermal homeostasis and proper skin barrier function.
  • Targeting Mysm1 or its downstream pathways could offer therapeutic strategies for skin development disorders.
Keywords:
DUBMysm1apoptosisepidermal barrierepidermal stem cellepigeneticshistone modificationp53p63skin

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