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Watson, James A., Alexander-Howden, Beatrice K., Hall, Theo S., Wear, Martin A., McGhie, Finlay 
ORCID: https://orcid.org/0009-0001-0358-0763, Clifford, Gillian, Wapenaar, Hannah, Zou, Juan, Bird, Adrian and Wilson, Marcus D.
(2026)
MeCP2 requires interactions with nucleosome linker DNA to read chromatin DNA methylation.
Nature Communications, 17 (1).
ISSN 2041-1723
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Abstract
Methyl-CpG-binding protein 2 (MeCP2) is a clinically important epigenetic reader that is essential for neuronal function, but how it binds methylated DNA within the protein-DNA complexes that comprise chromatin is unclear. Using designer nucleosomes, we observe that MeCP2 is able to engage methylated DNA at multiple sites on the nucleosome surface. Surprisingly, even methyl-cytosine placed in bent, histone-contacting, core nucleosomal DNA can be bound. However, we find that this ability requires interactions with inter-nucleosomal linker DNA. Nucleosome core DNA methylation reading involves regions of MeCP2 beyond its canonical methyl-CpG binding domain and we define a novel DNA-binding region in MeCP2 that is required for this function. We further demonstrate that histone H1 antagonises the MeCP2-nucleosome interactions by competing for linker DNA. Overall, our study reveals that MeCP2 gains access to methylated chromatinised DNA, independent of nucleosome structure, via essential nonspecific interactions with linker DNA.
| Item Type: | Article |
|---|---|
| Additional Information: | Data availability: Source Data for Figs. 1–7 and associated Supplementary Figs. 1–16 are provided with this paper. Reagents that support the findings of this study are available from the corresponding author upon reasonable request. The authors declare that all other data supporting the findings of this study are available within the paper and its supplementary and source information files. Crosslinking mass spectrometry data has been uploaded to the PRIDE database under identifier PXD064826. Protein structures used for modelling are available on the PDB, accession codes 3c2i and 3LZ0. Source data are provided with this paper. Code availability: The script for FRAP analysis using a custom macro with Fiji software is available on Zenodo (https://doi.org/10.5281/zenodo.2654601). |
| Faculty \ School: | Faculty of Science > School of Biological Sciences Faculty of Science |
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| Depositing User: | LivePure Connector |
| Date Deposited: | 23 Jun 2026 11:33 |
| Last Modified: | 01 Jul 2026 13:05 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/103477 |
| DOI: | 10.1038/s41467-026-71741-0 |
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