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

MeCP2 binds hydroxymethylated CA repeats Despites of decades of research on the Rett syndrome protein MeCP2, its function remains unclear. Ibrahim et al. show that MeCP2 is a hydroxymethylated cytosine-adenosine (CA) repeat-binding protein that modulates chromatin architecture at a distance from the transcription start site (see the Perspective by Zhou and Zoghbi). MeCP2 accumulates and spreads around modified CA repeats and competes for nucleosome occupancy. Loss of MeCP2 results in a widespread increase in nucleosome density inside lamina-associated domains and transcriptional dysregulation of genes enriched in CA repeats. These results shed light on the underlying molecular mechanism of Rett syndrome, a severe disease associated with mutations in MeCP2. Science , abd5581, this issue p. eabd5581 ; see also abj5027, p. 1390