Decision Letter: Loss of Dnmt3a and Dnmt3b Does Not Affect Epidermal Homeostasis but Promotes Squamous Transformation Through PPAR-γ

The study explored the role of Dnmt3a and Dnmt3b in skin tumorigenesis, revealing that their loss did not impact normal epidermal homeostasis but facilitated squamous transformation via increased PPAR-γ expression. The absence of Dnmt3a in keratinocytes led to faster hair regrowth and increased tumorigenesis post-DMBA treatment, suggesting Dnmt3a's role in maintaining hair follicles in a dormant state. Although the study lacked functional data linking Dnmt to gene regulation in tumorigenesis, it found that inhibiting PPAR-γ delayed tumor appearance and reduced tumor numbers in Dnmt3a-cKO mice, indicating a potential therapeutic approach for skin squamous cell carcinomas. The research also noted a slight increase in Cytosine to Thymine mutations in Dnmt3a-cKO tumors, with no significant changes in genomic instability. Overall, the findings suggested that Dnmt3a and Dnmt3b were not essential for normal epidermal differentiation but played a significant role in tumor initiation through the PPAR-γ pathway.