Dynamic DNA 6mA regulation in base unpairing regions of mammalian genome

【摘要】：N~6-methyladenine(6 mA) of DNA is an emerging epigenetic mark in mammalian genome.However,the biological role of 6 mA and the molecular pathways that exert its function remain unclear.Our structural and biochemical studies revealed that the 2-oxoglutarate-dependent oxygenase ALKBH1 functions as a nuclear eraser of 6 mA in unpairing regions of mammalian genome,such as Stress-Induced DNA Double Helix Destabilization(SIDD) regions.ssDNA-seq and DIP-seq analyses revealed significant co-occurrence of base unpairing regions with 6 mA in mouse genome.Levels of 6 mA undergo drastic fluctuation during the development of mouse trophoblast stem cells.Intriguingly,the presence of 6 mA repressed SIDD binding by the chromatin organizer SATB1,which is essential for gene regulation during trophoblast development in cell culture models and in vivo.Overall,our findings demonstrate an unexpected molecular mechanism for6 mA function that links DNA methylation,DNA unpairing dynamics,large chromatin domain organization through an eraser function of ALKBH1 and an"anti-reader" function of SATB1 during cell fate transitions in early development.