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

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Ibrahim, Abdulkhaleg | Papin, Christophe | Mohideen-Abdul, Kareem | Le Gras, Stéphanie | Stoll, Isabelle | Bronner, Christian | Dimitrov, Stefan | Klaholz, Bruno | Hamiche, Ali

Edité par CCSD ; American Association for the Advancement of Science (AAAS) -

International audience. 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.

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