Department of Dermatology and Allergic Diseases, University of Ulm, 89081 Ulm, Germany.
Institute and Out-Patient Clinic of Occupational, Social, and Environmental Medicine, Friedrich-Alexander University, 91054 Erlangen-Nürnberg, Germany.
Int J Mol Sci. 2018 Feb 28;19(3):687. doi: 10.3390/ijms19030687.
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-IntegrinCD34⁺ 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 Mysm1p53 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.
表皮的发育和稳态由一系列特定序列的转录因子和表观遗传修饰因子组成的复杂网络调控，这些因子协同调节祖细胞自我更新和终末分化之间的微妙平衡。为了研究组蛋白 H2A 去泛素化酶 2A-DUB/Mysm1 在皮肤中的作用，我们使用 Mysm1 缺陷小鼠和皮肤衍生的表皮细胞系统地分析了这种表观遗传调节剂的表达、发育功能和潜在相互作用。形态学上，Mysm1 缺陷小鼠的新生和幼鼠皮肤萎缩，表皮、真皮和皮下组织的厚度和细胞减少，与屏障功能改变有关。皮肤萎缩与 Mysm1 表皮和毛囊增殖率降低以及与野生型对照相比凋亡增加相关，同时 DNA 损伤标志物 γH2AX 增加。与 α6-整合素 CD34⁺表皮干细胞减少一致，体外检测到 Mysm1 表皮祖细胞的集落形成减少。在分子水平上，我们鉴定出 p53 是缺陷型 Mysm1 表皮细胞区室的潜在介质，导致促凋亡和抗增殖基因表达增加。在 Mysm1p53 双缺陷小鼠中，观察到皮肤萎缩显著恢复。通过量化经表皮水分流失来评估 Mysm1 发育中表皮的功能特性。总之，这项研究揭示了 2A-DUB/Mysm1 在表皮发育过程中抑制 p53 介导的抑制性程序中的作用。
