DNMT3B is a de novo DNA methyltransferase essential for establishing genome-wide methylation patterns during early development and gametogenesis 1. As a catalytic enzyme, DNMT3B transfers methyl groups to cytosine residues, with specific responsibility for methylating centromeric satellite repeats 1. Beyond DNA methylation catalysis, DNMT3B functions as a transcriptional corepressor through protein-protein interactions and regulates alternative splicing outcomes that influence downstream gene expression 23. DNMT3B activity is post-translationally regulated by S-nitrosylation, which attenuates its enzymatic function and prevents aberrant upregulation of proliferation genes like Cyclin D2 4. Mutations in DNMT3B cause ICF syndrome, characterized by hypomethylation of pericentromeric repeats 1. Disease associations include hematological malignancies through dysregulation of tumor suppressor gene methylation 5, facioscapulohumeral muscular dystrophy via DUX4 overexpression due to splicing dysregulation 3, endometriosis susceptibility through polymorphisms affecting methylation capacity 6, and intervertebral disc degeneration via altered m6A-regulated DNMT3B expression affecting E4F1 methylation 7. DNMT3B also influences metabolic homeostasis in pluripotent stem cells by regulating α-ketoglutarate levels and mitochondrial function 8.