The study investigates the role of the methyl-CpG-binding protein MeCP2 in linking DNA methylation to histone methylation. MeCP2 is known to recruit histone deacetylase (HDAC) activity, leading to chromatin remodeling and gene silencing. However, HDAC inhibitors do not fully relieve MeCP2-mediated repression, suggesting additional mechanisms. The authors show that MeCP2 associates with histone methyltransferase activity, specifically targeting lysine 9 (Lys9) of histone H3. This association is mediated by two characterized repression domains of MeCP2. Using the H19 gene, a MeCP2-regulated gene, the study demonstrates that MeCP2 facilitates H3 Lys9 methylation in the repressor region (the differentially methylated domain). ChIP experiments confirm that MeCP2 binding to nucleosomes in this region correlates with increased H3 Lys9 methylation. These findings indicate that MeCP2 reinforces the repressive chromatin state by bridging DNA methylation and histone methylation, potentially setting up a self-reinforcing cycle of repression.The study investigates the role of the methyl-CpG-binding protein MeCP2 in linking DNA methylation to histone methylation. MeCP2 is known to recruit histone deacetylase (HDAC) activity, leading to chromatin remodeling and gene silencing. However, HDAC inhibitors do not fully relieve MeCP2-mediated repression, suggesting additional mechanisms. The authors show that MeCP2 associates with histone methyltransferase activity, specifically targeting lysine 9 (Lys9) of histone H3. This association is mediated by two characterized repression domains of MeCP2. Using the H19 gene, a MeCP2-regulated gene, the study demonstrates that MeCP2 facilitates H3 Lys9 methylation in the repressor region (the differentially methylated domain). ChIP experiments confirm that MeCP2 binding to nucleosomes in this region correlates with increased H3 Lys9 methylation. These findings indicate that MeCP2 reinforces the repressive chromatin state by bridging DNA methylation and histone methylation, potentially setting up a self-reinforcing cycle of repression.