A role of protein conformational dynamics in mammalian DNA methylation

DNA methylation at the C-5 position of cytosine is an important epigenetic mechanism underpinning various cellular functions, such as heterochromatin assembly, gene expression, and cell fate determination. In mammals, DNA methylation mainly occurs in the context of CpG dinucleotide contexts. Establishment and maintenance of mammalian DNA methylation is orchestrated by two groups of functionally distinct enzymes: de novo DNA methyltransferases DNMT3A and DNMT3B and maintenance DNA methyltransferase DNMT1. For proper genomic methylation, both de novo and maintenance DNMTs are subjected to multilayered regulation by the chromatin environment, such as histone modifications and the methylation stiate of the CpG dinucleotide. Furthermore, DNA methylation is critically regulated by the accessory proteins of DNMTs, such as DNMT3L and DNMT3B3 for de novo methylation and E3 ubiquitin ligase UHRF1 for maintenance DNA methylation. Increasing structural, biochemical and cellular evidence has unveiled the intricate interplay between the conformational dynamics of DNMTs and their target specification in governing the dynamic DNA demethylation across the genome. This review focuses on recent advances in structural and functional understanding of DNMTs, emphasizing how the interplay between their intramolecular and intermolecular interactions modulates the conformational dynamics and function of the individual DNA methylation machinery, thereby shaping the dynamic DNA methylation landscape across the mammalian genome.