The importance of DNA methylation in neuronal function is highlighted by mutations in the neuronally enriched “reader” of DNA methylation, methyl-CpG-binding protein 2 (MECP2), causing Rett Syndrome (RTT), a severe neurodevelopmental disorder. Although MeCP2 displays broad genomic binding, gene expression changes in Mecp2 mutant mice are very subtle, and brain region-specific, making it difficult to determine how MeCP2 regulates gene expression. Therefore, we developed an approach to assess cell type-specific effects of Mecp2 mutations on the transcriptome, epigenome, and chromatin architecture to determine whether epigenomic features can explain gene misregulation in RTT. Differentially expressed genes (DEGs) in R106W Mecp2 mutants (R106W) are enriched for MeCP2 binding in the WT setting and are preferentially demethylated in R106W, suggesting that the loss of MeCP2 binding results in the exposure of unbound cytosines to demethylation, thus contributing to gene dysregulation. Given that DEGs are enriched for MeCP2 binding, we next determined unique features of DEGs to gain an understanding of why MeCP2 preferentially targets DEGs. We find that DEGs are cell type-specific, lowly expressed, and intragenically associated with heterochromatin, active enhancer, and CTCF chromatin states, suggesting that MeCP2 is essential for the regulation of lowly expressed genes. Upregulated and downregulated DEGs are differentially enriched for particular chromatin states, providing an insight into the directionality of gene dysregulation. Given the enrichment of DEGs for active enhancer and CTCF chromatin states, we next investigated transcription factor (TF) footprints and found thousands of altered TF footprints in R106W, with the CTCF motif being the most significantly associated. In WT, these sites are enriched for MeCP2 binding, and in R106W, these sites, which are associated with downregulated DEGs, become demethylated, enabling CTCF binding. This therefore suggests that MeCP2 can affect CTCF recruitment to chromatin. Given CTCF’s known role in chromatin organization, we employed Oligopaint and found large-scale condensation of euchromatin and heterochromatin, as well as decondensation of long genes. Together, this work provides insight into why DEGs are differentially susceptible to dysregulation in RTT and posits MeCP2 as a key player in global maintenance of the methylome and chromatin architecture for the preservation of neuronal gene expression.