Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
J Invest Dermatol. 2012 Dec;132(12):2681-90. doi: 10.1038/jid.2012.206. Epub 2012 Jul 5.
To examine the roles of epigenetic modulation on hair follicle regeneration, we generated mice with a K14-Cre-mediated loss of DNA methyltransferase 1 (DNMT1). The mutant shows an uneven epidermal thickness and alterations in hair follicle size. When formed, hair follicle architecture and differentiation appear normal. Hair subtypes exist but hair fibers are shorter and thinner. Hair numbers appear normal at birth but gradually decrease to <50% of control in 1-year-old mice. Sections of old mutant skin show follicles in prolonged telogen with hyperplastic sebaceous glands. Anagen follicles in mutants exhibit decreased proliferation and increased apoptosis in matrix transient-amplifying cells. Although K15-positive stem cells in the mutant bulge are comparable in number to the control, their ability to proliferate and become activated to form a hair germ is reduced. As mice age, residual DNMT activity declines further, and the probability of successful anagen reentry decreases, leading to progressive alopecia. Paradoxically, there is increased proliferation in the epidermis, which also shows aberrant differentiation. These results highlight the importance of DNA methylation in maintaining stem cell homeostasis during the development and regeneration of ectodermal organs.
为了研究表观遗传调控在毛囊再生中的作用，我们生成了 K14-Cre 介导的 DNA 甲基转移酶 1（DNMT1）缺失的小鼠。突变体表现出表皮厚度不均匀和毛囊大小改变。形成时，毛囊结构和分化似乎正常。存在不同的毛发类型，但毛发纤维更短、更细。出生时毛发数量正常，但在 1 岁时逐渐减少到对照组的<50%。老年突变体皮肤切片显示毛囊处于延长的休止期，皮脂腺增生。突变体中的生长期毛囊显示基质短暂扩增细胞增殖减少和凋亡增加。尽管突变体隆起部中的 K15 阳性干细胞数量与对照组相当，但它们增殖并激活形成毛原基的能力降低。随着小鼠年龄的增长，残余的 DNMT 活性进一步下降，成功进入生长期的可能性降低，导致进行性脱发。矛盾的是，表皮中的增殖增加，也表现出异常分化。这些结果强调了 DNA 甲基化在维持外胚层器官发育和再生过程中干细胞稳态的重要性。
