Dnmt3a associates with promoters and enhancers to protect epidermal stem cells from cancer [MeDIP-seq]

The de novo DNA methyltransferase Dnmt3a is mutated in human acute myeloid leukemia, and suppresses tumorigenesis in murine models of leukemia and lung cancer. Conversely, deregulation of the other de novo DNA methyltransferase, Dnmt3b, predominantly promotes tumorigenesis. However, the molecular mechanisms underlying the roles of Dnmt3a and Dnmt3b in cancer remain poorly understood. Using conditional knockout mice, here we show that Dnmt3a -- but not Dnmt3b -- strongly protects epidermal stem cells from carcinogen-induced tumor initiation, without affecting the progression of benign lesions to aggressive carcinomas. Only upon combined deletion of Dnmt3a and Dnmt3b, squamous cell carcinomas acquired a more aggressive fate and even became metastatic, indicating that Dnmt3b is tumor-suppressive, rather than pro-tumorigenic, in epidermal neoplasia. Mechanistically, Dnmt3a promotes the expression of epidermal differentiation genes by interacting with their enhancers, and inhibits the expression of lipid metabolism and cell proliferation genes by directly methylating their promoters. Altogether, we demonstrate that Dnmt3a, but not Dnmt3b, is critical for suppressing epidermal tumor initiation, while both enzymes prevent tumor progression. The study was performed to analyse the differentially methylated regions between skin tumors derived from mouse epidermis of wild type and Dnmt3a-deficient animals.