The De Novo DNA Methyltransferase DNMT3A Is Required for Epidermal Homeostasis

The study found that the de novo DNA methyltransferase DNMT3A is essential for maintaining epidermal homeostasis and proper hair follicle cycling. Mice expressing an inducible DNMT3AR882H transgene, which has a dominant negative effect on wild type DNMT3A activity, developed alopecia that was reversible upon cessation of transgene expression. Dnmt3a was found to be the most abundantly expressed de novo DNA methyltransferase in the skin, with strong expression during hair follicle morphogenesis in the post-natal period and transient expression upon provoked hair cycling. Mice with epidermis-specific Dnmt3a deficiency showed no gross abnormalities initially but had a decreased threshold for hair cycle entry upon serial depilation. Constitutive Dnmt3a deficiency led to severe growth retardation and death within 2-3 weeks after birth, along with a variably penetrant alopecia phenotype. Skin grafts from Dnmt3a deficient mice often failed to exhibit normal hair growth. Whole genome bisulfite sequencing of skin samples revealed many tissue-specific, focally hypomethylated regions in Dnmt3a deficient skin, indicating the importance of DNMT3A-mediated DNA methylation for hair follicle function and skin health.