Fig. 7: Working model for normal MeCP2 function on chromatin and its dysregulation in disease.

a, WT MeCP2 rapidly scans unmethylated bare DNA regions, often in oligomeric units, and becomes trapped upon encountering methyl-CpG sites, where it performs methylation-dependent activities such as recruiting transcriptional co-repressors. In contrast, MeCP2 stably engages with nucleosomes and protects them from mechanical perturbation. This interaction also facilitates the recruitment of binding partners of MeCP2 to nucleosome sites. Nucleosomes also serve as molecular sponges that efficiently capture MeCP2, reducing the pool of MeCP2 molecules available to bind bare DNA. b, Aberrant function of RTT-causing MeCP2 mutants can be manifested through diverse mechanisms, including slowed or halted search on bare DNA, reduced binding to methyl-DNA, reduced nucleosome targeting, weakened nucleosome stabilization, impaired effector recruitment and imbalanced chromatin distribution. These abnormal MeCP2 behaviors may contribute to the molecular basis for MeCP2-related disorders such as RTT and MDS.