DNA N⁶-methyldeoxyadenosine in mammals and human disease

N⁶-methyladenine (6mA) is the most prevalent DNA modification in prokaryotes. However, its presence and significance in eukaryotes remain elusive. Recently, with methodology advances in detection and sequencing of 6mA in eukaryotes, 6mA is back in the spotlight. Although multiple studies have reported that 6mA is an important epigenetic mark in eukaryotes and plays a regulatory role in DNA transcription, transposon activation, stress response, and other bioprocesses, there are some discrepancies in the current literature. We review the recent advances in 6mA research in eukaryotes, especially in mammals. In particular, we describe the abundance/distribution of 6mA, its potential role in regulating gene expression, identified regulators, and pathological roles in human diseases, especially in cancer. The limitations faced by the field and future perspectives in 6mA research are also discussed.