MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion

Abdulkhaleg Ibrahim (1, 2) , Christophe Papin (1, 2) , Kareem Mohideen-Abdul (2, 1) , Stéphanie Le Gras (1, 2) , Isabelle Stoll (1, 2) , Christian Bronner (1, 2) , Stefan Dimitrov (3, 4) , Bruno Klaholz (2, 1) , Ali Hamiche (1, 2)

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 Inserm U964 - CNRS UMR7104 - IGBMC - Centre for Integrative Biology - CBI
3 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
4 BAS - Bulgarian Academy of Sciences

The Rett syndrome protein MeCP2 was described as a methyl-CpG-binding protein, but its exact function remains unknown. Here we show that mouse MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats. Depletion of MeCP2 alters chromatin organization of CA repeats and lamina-associated domains and results in nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation. The structure of MeCP2 in complex with a hydroxymethylated CA repeat reveals a characteristic DNA shape, with considerably modified geometry at the 5-hydroxymethylcytosine, which is recognized specifically by Arg133, a key residue whose mutation causes Rett syndrome. Our work identifies MeCP2 as a microsatellite DNA binding protein that targets the 5hmC-modified CA-rich strand and maintains genome regions nucleosome-free, suggesting a role for MeCP2 dysfunction in Rett syndrome.

Domaines: Sciences du Vivant [q-bio]

Abdulkhaleg Ibrahim, Christophe Papin, Kareem Mohideen-Abdul, Stéphanie Le Gras, Isabelle Stoll, et al.. MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion. Science, 2021, 372 (6549), ⟨10.1126/science.abd5581⟩. ⟨inserm-03376640⟩