Single-cell multi-omic detection of DNA methylation and histone modifications reconstructs the dynamics of epigenomic maintenance

Christoph Geisenberger; Jeroen van den Berg; Vincent van Batenburg; Buys de Barbanson; Anna Lyubimova; Joe Verity-Legg; Xiufei Chen; Yibin Liu; Chun Xiao Song; Jeroen de Ridder; Alexander van Oudenaarden

doi:10.1038/s41592-025-02847-4

Single-cell multi-omic detection of DNA methylation and histone modifications reconstructs the dynamics of epigenomic maintenance

Christoph Geisenberger
, Jeroen van den Berg^*
, Vincent van Batenburg
, Buys de Barbanson
, Anna Lyubimova
, Joe Verity-Legg
, Xiufei Chen
, Yibin Liu
, Chun Xiao Song
, Jeroen de Ridder
, Alexander van Oudenaarden^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

DNA methylation and histone modifications encode epigenetic information. Recently, major progress was made to measure either mark at a single-cell resolution; however, a method for simultaneous detection is lacking, preventing study of their interactions. Here, to bridge this gap, we developed scEpi²-seq. Our technique provides a readout of histone modifications and DNA methylation at the single-cell and single-molecule level. Application in a cell line with the FUCCI cell cycle reporter system reveals how DNA methylation maintenance is influenced by the local chromatin context. In addition, profiling of H3K27me3 and DNA methylation in the mouse intestine yields insights into epigenetic interactions during cell type specification. Differentially methylated regions also demonstrated independent cell-type regulation in addition to H3K27me3 regulation, which reinforces that CpG methylation acts as an additional layer of control in facultative heterochromatin.

Original language	English
Pages (from-to)	2042-2051
Number of pages	10
Journal	Nature Methods
Volume	22
Issue number	10
Early online date	2025
DOIs	https://doi.org/10.1038/s41592-025-02847-4
Publication status	Published - Oct 2025

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Single-cell multi-omic detection of DNA methylation and histone modifications reconstructs the dynamics of epigenomic maintenanceFinal published version, 28.8 MBLicence: CC BY-NC-ND

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Geisenberger, C., van den Berg, J., van Batenburg, V., de Barbanson, B., Lyubimova, A., Verity-Legg, J., Chen, X., Liu, Y., Song, C. X., de Ridder, J., & van Oudenaarden, A. (2025). Single-cell multi-omic detection of DNA methylation and histone modifications reconstructs the dynamics of epigenomic maintenance. Nature Methods, 22(10), 2042-2051. https://doi.org/10.1038/s41592-025-02847-4

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title = "Single-cell multi-omic detection of DNA methylation and histone modifications reconstructs the dynamics of epigenomic maintenance",

abstract = "DNA methylation and histone modifications encode epigenetic information. Recently, major progress was made to measure either mark at a single-cell resolution; however, a method for simultaneous detection is lacking, preventing study of their interactions. Here, to bridge this gap, we developed scEpi2-seq. Our technique provides a readout of histone modifications and DNA methylation at the single-cell and single-molecule level. Application in a cell line with the FUCCI cell cycle reporter system reveals how DNA methylation maintenance is influenced by the local chromatin context. In addition, profiling of H3K27me3 and DNA methylation in the mouse intestine yields insights into epigenetic interactions during cell type specification. Differentially methylated regions also demonstrated independent cell-type regulation in addition to H3K27me3 regulation, which reinforces that CpG methylation acts as an additional layer of control in facultative heterochromatin.",

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Geisenberger, C, van den Berg, J, van Batenburg, V, de Barbanson, B, Lyubimova, A, Verity-Legg, J, Chen, X, Liu, Y, Song, CX, de Ridder, J & van Oudenaarden, A 2025, 'Single-cell multi-omic detection of DNA methylation and histone modifications reconstructs the dynamics of epigenomic maintenance', Nature Methods, vol. 22, no. 10, pp. 2042-2051. https://doi.org/10.1038/s41592-025-02847-4

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AU - van den Berg, Jeroen

AU - van Batenburg, Vincent

AU - de Barbanson, Buys

AU - Lyubimova, Anna

AU - Verity-Legg, Joe

AU - Chen, Xiufei

AU - Liu, Yibin

AU - Song, Chun Xiao

AU - de Ridder, Jeroen

AU - van Oudenaarden, Alexander

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AB - DNA methylation and histone modifications encode epigenetic information. Recently, major progress was made to measure either mark at a single-cell resolution; however, a method for simultaneous detection is lacking, preventing study of their interactions. Here, to bridge this gap, we developed scEpi2-seq. Our technique provides a readout of histone modifications and DNA methylation at the single-cell and single-molecule level. Application in a cell line with the FUCCI cell cycle reporter system reveals how DNA methylation maintenance is influenced by the local chromatin context. In addition, profiling of H3K27me3 and DNA methylation in the mouse intestine yields insights into epigenetic interactions during cell type specification. Differentially methylated regions also demonstrated independent cell-type regulation in addition to H3K27me3 regulation, which reinforces that CpG methylation acts as an additional layer of control in facultative heterochromatin.

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JF - Nature Methods

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Single-cell multi-omic detection of DNA methylation and histone modifications reconstructs the dynamics of epigenomic maintenance

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Author Correction: Single-cell multi-omic detection of DNA methylation and histone modifications reconstructs the dynamics of epigenomic maintenance (Nature Methods, (2025), 22, 10, (2042-2051), 10.1038/s41592-025-02847-4)

Correction to: Single-cell multi-omic detection of DNA methylation and histone modifications reconstructs the dynamics of epigenomic maintenance (Nature Methods, (2025), 22, 10, (2042-2051), 10.1038/s41592-025-02847-4)

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