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

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 Burdon and Adrian Bird ()
Additional contact information
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
Claude Libert: VIB
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

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47395-1

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