Loops, crosstalk, and compartmentalization: it takes many layers to regulate DNA methylation

DNA methylation is a conserved epigenetic modification associated with transposon silencing and gene regulation. The stability of this modification relies on intimate connections between DNA and histone modifications that generate self-reinforcing loops wherein the presence of one mark promotes the other. However, it is becoming increasingly clear that the efficiency of these loops is affected by cross-talk between pathways and by chromatin accessibility, which is heavily influenced by histone variants. Focusing primarily on plants, this review provides an update on the aforementioned self-reinforcing loops, highlights recent advances in understanding how DNA methylation pathways are restricted to prevent encroachment on genes, and discusses the roles of histone variants in compartmentalizing epigenetic pathways within the genome. This multilayered approach facilitates two essential, yet opposing functions, the ability to maintain heritable DNA methylation patterns while retaining the flexibility to modify these patterns during development.