De Novo DNMTs and DNA Methylation: Novel Insights into Disease Pathogenesis and Therapy from Epigenomics.

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 hypo- and hyper-methylation sites provide targets for the epigenetic therapy. Generally, we can distinguish two groups of epi-drugs, (i) covalently binding to the DNA, bringing higher cytotoxic effect and (ii) allosteric DNMT inhibitors, showing less side-effects. Moreover, targeting pharmacological treatment on DNMT3B inhibition enhances chemotherapeutic effect and gives more chances for patients' 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.