Now and then in eukaryotic DNA methylation

Since the mid-1970s, increasingly innovative methods to detect DNA methylation provided detailed information about its distribution, functions, and dynamics. As a result, new concepts were formulated and older ones were revised, transforming our understanding of the associated biology and catalyzing unprecedented advances in biomedical research, drug development, anthropology, and evolutionary biology. In this review, we discuss a few of the most notable advances, which are intimately intertwined with the study of DNA methylation, with a particular emphasis on the past three decades. Examples of these strides include elucidating the intricacies of 5-methylcytosine (5-mC) oxidation, which are at the core of the reversibility of this epigenetic modification; the three-dimensional structural characterization of eukaryotic DNA methyltransferases, which offered insights into the mechanisms that explain several disease-associated mutations; a more in-depth understanding of DNA methylation in development and disease; the possibility to learn about the biology of extinct species; the development of epigenetic clocks and their use to interrogate aging and disease; and the emergence of epigenetic biomarkers and therapies.