Mechanisms and biological roles of DNA methyltransferases and DNA methylation: From past achievements to future challenges

DNA methylation and DNA methyltransferases (MTases) – the enzymes that introduce the methylation mark into the DNA – have been studied for almost 70 years. In this chapter, we review key developments in the field that led to our current understanding of the structures and mechanisms of DNA MTases and the essential biological role of DNA methylation, including the discovery of DNA methylation and DNA MTases, the cloning and sequence analysis of bacterial and eukaryotic MTases, and the elucidation of their structure, mechanism, and regulation. We describe genetic studies that contributed greatly to the evolving views on the role of DNA methylation in human development and diseases, the invention of methods for the genome-wide analysis of DNA methylation, and the biochemical identification of DNA MTases and the family of TET enzymes, which are involved in DNA demethylation. We finish by highlighting critical questions for the next years of research in the field