The concurrence of DNA methylation and demethylation is associated with transcription regulation

The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying 'methylation concurrence' by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation concurrence is strongly correlated with gene expression. Notably, elevated methylation concurrence in tumors is associated with the repression of 40 similar to 60% of tumor suppressor genes, which cannot be explained by promoter hypermethylation alone. Furthermore, methylation concurrence can be used to stratify large undermethylated regions with negligible differences in average methylation into two subgroups with distinct chromatin accessibility and gene regulation patterns. Together, methylation concurrence represents a unique methylation metric important for transcription regulation and is distinct from conventional metrics, such as average methylation and methylation variation.

Automated summary

The mammalian DNA methylome is regulated by methylation and demethylation processes, which have a direct impact on gene expression. Methylation concurrence, measured by the percentage of unmethylated CpGs within partially methylated reads, is strongly correlated with gene expression and can be used to stratify DNA regions based on chromatin accessibility and gene regulation patterns. Methylation concurrence represents a unique methylation metric important for transcription regulation, distinct from conventional metrics such as average methylation and methylation variation.