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<p>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.</p>

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MeCP2 requires interactions with nucleosome linker DNA to read chromatin DNA methylation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月17日

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  • James A. Watson,
  • Beatrice K. Alexander-Howden,
  • Theo S. Hall,
  • Martin A. Wear,
  • Finlay McGhie,
  • Gillian Clifford,
  • Hannah Wapenaar,
  • Juan Zou,
  • Adrian Bird,
  • Marcus D. Wilson

摘要

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.