DNA hypomethylation is a feature of epidermal cells from aged and sun-exposed skin, but the mechanisms responsible for this methylation loss are not known. Dnmt3a is the dominant de novo DNA methyltransferase in the skin; while epidermal Dnmt3a deficiency creates a premalignant state in which keratinocytes are more easily transformed by topical mutagens, the conditions responsible for this increased susceptibility to transformation are not well understood. Using whole genome bisulfite sequencing, we identified a focal, canonical DNA hypomethylation phenotype in the epidermal cells of Dnmt3a-deficient mice. Single-cell transcriptomic analysis revealed an increased proportion of cells with a proliferative gene expression signature, while other populations in the skin were relatively unchanged. Although total DNMT3A deficiency has not been described in human disease states, rare patients with an overgrowth syndrome associated with behavioral abnormalities and an increased risk of cancer often have heterozygous, germline mutations in DNMT3A that reduce its function (Tatton-Brown Rahman syndrome [TBRS]). We evaluated the DNA methylation phenotype of the skin from a TBRS patient with a germline DNMT3A^R882H mutation, which encodes a dominant-negative protein that reduces its methyltransferase function by ∼80%. We detected a focal, canonical hypomethylation phenotype that revealed considerable overlap with hypomethylated regions found in Dnmt3a-deficient mouse skin. Together, these data suggest that DNMT3A loss creates a premalignant epigenetic state associated with a hyperproliferative phenotype in the skin and further suggest that DNMT3A acts as a tumor suppressor in the skin.

DNA 低甲基化是老化和暴露在阳光下的皮肤的表皮细胞的一个特征，但导致这种甲基化丢失的机制尚不清楚。Dnmt3a 是皮肤中占主导地位的从头 DNA 甲基转移酶；虽然表皮 Dnmt3a 缺乏会产生一种癌前状态，其中角质形成细胞更容易被局部诱变剂转化，但导致这种转化易感性增加的条件尚不清楚。使用全基因组亚硫酸氢盐测序，我们在 Dnmt3a 缺陷小鼠的表皮细胞中鉴定了一个焦点、典型的 DNA 低甲基化表型。单细胞转录组学分析显示，具有增殖基因表达特征的细胞比例增加，而皮肤中的其他细胞群则相对不变。降低其功能的DNMT3A（Tatton-Brown Rahman 综合征 [TBRS]）。我们评估了具有生殖系DNMT3A ^R882H突变的 TBRS 患者皮肤的 DNA 甲基化表型，该突变编码一种显性^失活蛋白，将其甲基转移酶功能降低约 80%。我们检测到一种局灶性、典型的低甲基化表型，该表型显示与 Dnmt3a 缺陷小鼠皮肤中发现的低甲基化区域有相当大的重叠。总之，这些数据表明 DNMT3A 缺失会产生与皮肤过度增殖表型相关的癌前表观遗传状态，并进一步表明 DNMT3A 在皮肤中充当肿瘤抑制因子。