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MeCP2 binds to methylated DNA independently of phase separation and heterochromatin organisation

Author

Listed:
  • Raphaël Pantier

    (University of Edinburgh, Michael Swann Building, Max Born Crescent, The King’s Buildings)

  • Megan Brown

    (University of Edinburgh, Michael Swann Building, Max Born Crescent, The King’s Buildings)

  • Sicheng Han

    (University of Edinburgh, Michael Swann Building, Max Born Crescent, The King’s Buildings)

  • Katie Paton

    (University of Edinburgh, Michael Swann Building, Max Born Crescent, The King’s Buildings)

  • Stephen Meek

    (University of Edinburgh, Easter Bush)

  • Thomas Montavon

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Nicholas Shukeir

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Toni McHugh

    (University of Edinburgh, Michael Swann Building, Max Born Crescent, The King’s Buildings)

  • David A. Kelly

    (University of Edinburgh, Michael Swann Building, Max Born Crescent, The King’s Buildings)

  • Tino Hochepied

    (VIB
    Ghent University)

  • Claude Libert

    (VIB
    Ghent University)

  • Thomas Jenuwein

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Tom Burdon

    (University of Edinburgh, Easter Bush)

  • Adrian Bird

    (University of Edinburgh, Michael Swann Building, Max Born Crescent, The King’s Buildings)

Abstract

Correlative evidence has suggested that the methyl-CpG-binding protein MeCP2 contributes to the formation of heterochromatin condensates via liquid-liquid phase separation. This interpretation has been reinforced by the observation that heterochromatin, DNA methylation and MeCP2 co-localise within prominent foci in mouse cells. The findings presented here revise this view. MeCP2 localisation is independent of heterochromatin as MeCP2 foci persist even when heterochromatin organisation is disrupted. Additionally, MeCP2 foci fail to show hallmarks of phase separation in live cells. Importantly, we find that mouse cellular models are highly atypical as MeCP2 distribution is diffuse in most mammalian species, including humans. Notably, MeCP2 foci are absent in Mus spretus which is a mouse subspecies lacking methylated satellite DNA repeats. We conclude that MeCP2 has no intrinsic tendency to form condensates and its localisation is independent of heterochromatin. Instead, the distribution of MeCP2 in the nucleus is primarily determined by global DNA methylation patterns.

Suggested Citation

  • Raphaël Pantier & Megan Brown & Sicheng Han & Katie Paton & Stephen Meek & Thomas Montavon & Nicholas Shukeir & Toni McHugh & David A. Kelly & Tino Hochepied & Claude Libert & Thomas Jenuwein & Tom Bu, 2024. "MeCP2 binds to methylated DNA independently of phase separation and heterochromatin organisation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47395-1
    DOI: 10.1038/s41467-024-47395-1
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    References listed on IDEAS

    as
    1. Yan Jiang & Xing Fu & Yuhan Zhang & Shen-Fei Wang & Hong Zhu & Wei-Kang Wang & Lin Zhang & Ping Wu & Catherine C. L. Wong & Jinsong Li & Jinbiao Ma & Ji-Song Guan & Ying Huang & Jingyi Hui, 2021. "Rett syndrome linked to defects in forming the MeCP2/Rbfox/LASR complex in mouse models," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
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    3. Rebekah Tillotson & Jim Selfridge & Martha V. Koerner & Kamal K. E. Gadalla & Jacky Guy & Dina De Sousa & Ralph D. Hector & Stuart R. Cobb & Adrian Bird, 2017. "Radically truncated MeCP2 rescues Rett syndrome-like neurological defects," Nature, Nature, vol. 550(7676), pages 398-401, October.
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