Linking DNA Methyltransferases to Epigenetic Marks and Nucleosome Structure Genome-wide in Human Tumor Cells

DNA methylation, mediated by the combined action of three DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B), is essential for mammalian development and is a major contributor to cellular transformation. To elucidate how DNA methylation is targeted, we mapped the genome-wide localization of all DNMTs and methylation, and examined the relationships among these markers, histone modifications, and nucleosome structure in a pluripotent human tumor cell line in its undifferentiated and differentiated states. Our findings reveal a strong link between DNMTs and transcribed loci, and that DNA methylation is not a simple sum of DNMT localization patterns. A comparison of the epigenomes of normal and cancerous stem cells, and pluripotent and differentiated states shows that the presence of at least two DNMTs is strongly associated with loci targeted for DNA hypermethylation. Taken together, these results shed important light on the determinants of DNA methylation and how it may become disrupted in cancer cells. [Display omitted] ► DNMT and DNA-Me maps are established in a pluripotent cancer cell line ► DNMT binding is strongly linked to transcribed loci, exons, and nucleosomes ► DNA-Me patterns are not simply the sum of DNMT binding patterns ► Targeting of DNA hypermethylation is influenced by DNMT binding and histone marks Mechanisms that regulate the targeting and activity of DNA methyltransferases (DNMTs) and their mark, 5-methylcytosine, remain largely unknown. Deregulation of this targeting is a ubiquitous feature of cancer cells. Choi, Robertson, and colleagues map the localization of all enzymatically active DNMTs in cancer cells in different states, and probe the relationships among DNMT binding, epigenetic marks, transcription, and nucleosome positioning. They show that DNMTs are surprisingly enriched in transcriptionally active genes and their binding is predictive of loci that sustain differentiation-associated hypermethylation events.