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bioRxiv · 10.1101/2025.11.17.688913

DNA methylation landscapes in human cells and their chromatin determinants

Cui, W.·Huang, Z.·Pfeifer, G. P.
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Abstract

DNA methylation patterns are established during development and are propagated in a cell type specific manner, but these patterns may become aberrant during aging and cancer. Regions of alternating high and moderate to low levels of DNA methylation exist along all chromosomes in human cells. It is unclear how these distinct DNA methylation blocks are established. Here we have profiled DNA methylation at single base resolution and various histone modifications in human bronchial epithelial cells. We found that many regions of lower DNA methylation are characterized by presence of the Polycomb repressive complex 2 (PRC2) mark histone H3 K27 trimethylation but less so by the PRC1 mark histone H2A K119 monoubiquitylation. These same PRC2-marked regions also showed a depletion of histone H3K36 di- and tri-methylation. Since H3K36me2 and H3K36me3 are recognized by the reader domains of the DNA methyltransferases DNMT3A and DNMT3B and H3K36 methylation is a block to the PRC2 methyltransferases, these crosstalks explain the stable maintenance and antagonism of H3K27me3 and DNA methylation domains. The data give insight into how DNA methylation patterns are established in human cells. We discuss these findings and their potential relevance for altered DNA methylation patterns seen in aging tissues and in cancer cells.

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Cui, W., Huang, Z., Pfeifer, G. P.. 2025-11-17. DNA methylation landscapes in human cells and their chromatin determinants. https://doi.org/10.1101/2025.11.17.688913

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