The role of substrate deformation in context‐dependent non‐CG DNA methylation

Abstract

Cytosine‐5 DNA methylation is a major epigenetic mechanism that is important for gene regulation and genome stability. Across evolution, the DNA methylation pathways have diversified between different kingdoms. For instance, DNA methylation in mammals predominantly occurs in the context of CG dinucleotides, established by de novo DNA methyltransferases DNMT3A and DNMT3B and maintained by DNMT1. In contrast, DNA methylation in plants occurs in all three sequence contexts in plants, namely CG, CHG and CHH (H = A, C, or T), with CHG and CHH methylation maintained by CHROMOMETHYLASES (CMTs) and Domains Rearranged Methyltransferase 2 (DRM2). Emerging evidence reveals high context‐dependence of non‐CG methylation in plants: both CHG and CHH methylation is enriched with an A or T nucleotide at the +1‐flanking site, providing a mechanism in reinforcing DNA methylation at specific chromatin domains, such as AT‐rich TEs. To understand the context‐dependency of plant non‐CG methylation, we recently characterized the structural basis for the DRM2‐ and CMT3‐mediated non‐CG methylation. Remarkably, DRM2‐ and CMT‐mediated DNA methylation both involve intercalation‐induced base distortion at the +1 target‐flanking site. The conformational energy penalty associated with this DNA deformation is mostly stabilized by van der Waals contacts, rather than base‐specific hydrogen‐bonding interactions that were previously observed for mammalian DNMTs, allowing the potential influence of nucleotide composition at the +1 site on DRM2‐ and CMT‐mediated methylation. These findings establish a link between DNA deformation and context‐dependent non‐CG DNA methylation in plants, providing a new paradigm for the evolutionarily diversified DNA methylation mechanisms.