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

Abstract

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 40~60% 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.

Changes in DNA methylation hallmark alterations in chromatin accessibility and gene expression for eye lens differentiation

“…Differentially methylated regions (DMRs) are established regulators of major gene expression changes [ 8 , 49 , 50 ]. Our analysis identified 7621 total mCG DMRs across the E13 embryonic chick lens genome.…”

5-methylcytosine turnover: Mechanisms and therapeutic implications in cancer

“…This metric highlighted the antagonizing activities of TETs and DNMTs, especially near TSS-proximal regions. Compared with other conventional metrics such as average methylation and the methylation variation, methylation occurrence is able to detect larger sets of regulatory regions and appears to be a better predictor of gene expression (Shi et al, 2021). These results demonstrate that DNA methylation can be modelized as a highly dynamic and context-specific process occurring mostly at DMRs, including enhancer regions characterized by oscillations in DNA methylation levels.…”

“…To get through the challenges faced by bulk measurements and sequence dependent approaches, novel experimental methods combining single-cell sequencing, modeling, and knock-out of (de)methylation enzymes revealed highly dynamic methylation changes in early development both in vitro and in vivo ( Rulands et al, 2018 ; Song et al, 2019 ; Charlton et al, 2020 ; De Riso et al, 2020 ; Shi et al, 2021 ). The co-engagement of DNMTs and TET enzymes on the same DNA molecule has been evidenced not long ago by Rulands et al by using single-cell sequencing and a modelling method.…”

“…Methyltransition revealed a programmed epigenetic heterogeneity in early embryos which is defined by the first DNA methylation status at the zygote phase in development ( Zhao et al, 2020 ). Recently, a new quantitative measure of DNA methylation known as the methylation occurrence ratio has been developed to study the interplay between DNA methylation and transcription regulation ( Shi et al, 2021 ). This metric highlighted the antagonizing activities of TETs and DNMTs, especially near TSS-proximal regions.…”

Airway Wall Remodeling in Childhood Asthma—A Personalized Perspective from Cell Type-Specific Biology

“…In the DNA, clusters of cytosine and guanine dinucleotides, also named CpGs-island, were indicated as the preferred target for methylation [117]. A multi-cohort epigenome meta-analysis compared DNA-methylation in four age groups of asthmatics: (i) newborns, (ii) 4 years old, (iii) 16 years old, and (iv) adults [118].…”