Epigenetic networks coordinate DNA methylation across the genome

The epigenetic landscape governs cell fate decisions during development, aging, and disease. Despite considerable progress in the understanding of DNA methylation (DNAm), the mechanisms that orchestrate its coordinated regulation across the genome remain largely elusive. Recent breakthroughs in sequencing technologies and epigenetic editing tools enable a more comprehensive exploration of these epigenetic interactions. Regulation of DNAm seems to be organized within epigenetic networks characterized by complex feedback mechanisms acting locally, between homologous alleles, and across the entire genome. This crosstalk is facilitated by an interplay of various molecular components, including distinct variants of epigenetic writers and erasers; methylation-sensitive binding of transcription factors and other regulatory proteins that recruit DNA methyltransferases; cross-regulation between DNAm and the histone code; three-dimensional (3D) chromatin conformation; regulatory effects mediated by long non-coding RNAs (lncRNAs); and potentially by assimilation during homologous recombination events. This review explores how these diverse epigenetic mechanisms interact to collectively shape the methylome and thereby control developmental and disease processes.