DNA methylation in human disease: from biological mechanisms to clinical applications

This review provides an overview of DNA methylation, beginning with its chemical modification and biological role, and progressing to its clinical relevance. It is designed for readers without prior knowledge of the field and is divided into two main sections: Biological Mechanisms and Clinical Applications. The first section explores the molecular and biological mechanisms underlying DNA methylation. It examines the different types of methylation marks and the enzymes responsible for their addition and removal. The process is driven by the recruitment and activation of DNA methylation-modulating enzymes, with the nucleosome barrier playing a significant role. A key aspect discussed is the resetting of DNA methylation patterns during development. This resetting occurs in two distinct waves: the first in germ cells and the second after fertilization, which is associated with cellular differentiation and the establishment of transcriptional programs in various lineages. The typical locations and patterns of DNA methylation in normal somatic cells are described. Additionally, the review explains the diverse molecular functions of DNA methylation. These functions are categorized as immediate effects, such as changes in binding of factors to specific DNA sequences, and remote effects, including transcriptional modulation resulting from these changes. The clinical application section focuses on diseases linked to abnormal DNA methylation. These include developmental syndromes caused by inherited mutations in genes encoding methylation modulators, as well as cancers characterized by somatic mutations (such as TET2 or DNMT3A) and abnormal methylation patterns in various diseases. The review discusses the broad uses of DNA methylation assessment. Applications include its role as an epigenetic clock for estimating biological age, its utility in cancer screening and early detection, subcategorization of cancer types, determination of tumor origin, and diagnosis in cases with unclear histology. Finally, the review concludes with a description of DNA methylation-targeting agents used in hematologic malignancies and their limited effectiveness in solid tumors. It briefly addresses the ongoing development of future drugs designed to modulate DNA methylation.