# DNA Methylation Concurrence, Independent of DNA Methylation Ratios, Is Associated with Chromatin Accessibility and 3D Genome Architecture

## TL;DR

This study shows that DNA methylation concurrence, not just methylation levels, is linked to chromatin structure and gene regulation in healthy and tumor tissues.

## Contribution

The study introduces DNA methylation concurrence (MCR) as a novel metric for identifying biologically meaningful methylation patterns.

## Key findings

- DNA methylation concurrence (MCR) captures tissue-specific features independent of methylation ratios.
- Regions with decreased MCR in tumors overlap with chromatin accessibility sites and active regulatory elements.
- MCDRs facilitate CTCF binding and long-range chromatin interactions, contributing to gene regulation.

## Abstract

Multiple metrics for read-level DNA methylation pattern analysis have provided new insights into DNA methylation modifications. However, the performance of these metrics and their relationship with DNA methylation ratios in identifying biologically meaningful regions have remained unclear. Here, we systematically benchmarked five read-level DNA methylation metrics using whole-genome bisulfite sequencing data from 59 individuals across six healthy tissue types and six tumor types. We found that DNA methylation concurrence (MCR) effectively captured tissue-specific features independent of the DNA methylation ratios. Regions that exhibited decreased MCR (MCDRs) in tumors were significantly enriched in promoter and intergenic regions and strongly overlapped with tumor-gained chromatin accessibility sites. The further analysis of histone modifications, including H3K4me3, H3K27ac, and H3K9ac, confirmed that MCDRs marked active gene regulatory elements. Motif enrichment analysis revealed a strong preference for CTCF binding within MCDRs. Additionally, 3D genome analysis supported a model in which MCDRs, independent of DNA methylation ratios, contribute to active gene regulation by facilitating CTCF binding and long-range chromatin interactions.