2A-DUB/ Mysm1 regulates epidermal development in part by suppressing p53-mediated programs

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 gamma H2AX. In accordance with diminished alpha 6-Integrin(high+)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.