DNA methylation plays an important role in epigenetics signaling, having an impact on gene regulation, chromatin structure
and development. Within the family of de novo DNA methyltransferases two active enzymes, DNMT3A and DNMT3B, are responsible
for the establishment of the proper cytosine methylation profile during development. Defects in DNMT3s function correlate with pathogenesis
and progression of monogenic diseases and cancers. Among monogenic diseases, Immunodeficiency, Centromeric instability and
Facial anomalies (ICF) syndrome is the only Mendelian disorder associated with DNMT3B mutations and DNA methylation defects of
satellite and non-satellite regions. Similar CpG hypomethylation of the repetitive elements and gene-specific hypermethylation are observed
in many types of cancer.
DNA hyper-methylation sites provide targets for the epigenetic therapy. Generally, we can distinguish two groups of epi-drugs affecting
DNMTs activity, i) nucleoside inhibitors, covalently trapping the enzymes, and bringing higher cytotoxic effect and (ii) nonnucleoside
inhibitors, which block their active sites, showing less side-effects. Moreover, combining drugs targeting chromatin and those targeting
DNA methylation enhances the efficacy of the therapy and gives more chances of patient recovery. However, development of more specific
and effective epigenetic therapies requires more complete understanding of epigenomic landscapes. Here, we give an overview of
the recent findings in the epigenomics field, focusing on those related to DNA methylation defects in disease pathogenesis and therapy.