MeCP2, a key contributor to neurological disease, activates and represses transcription. Mutations in the gene encoding MeCP2 cause Rett syndrome, a neurodevelopmental disorder. Loss of function or increased dosage of MeCP2 leads to various neuropsychiatric disorders. This study examined gene expression in the hypothalamus of mice with MeCP2 deficiency or overexpression. It found that MeCP2 dysfunction alters the expression of thousands of genes, with most (85%) being activated. MeCP2 binds to promoters of six genes and associates with CREB1 at activated targets but not repressed ones. These findings suggest MeCP2 functions as both an activator and repressor of transcription. MeCP2 is a transcriptional repressor that binds to methylated CpG dinucleotides and recruits corepressors. In mice, MeCP2 deficiency leads to neurological dysfunction, while overexpression causes similar symptoms to human MeCP2 duplication syndrome. The study used microarray analysis to compare gene expression in the hypothalamus of MeCP2-Tg and Mecp2-null mice, revealing that 2,184 genes were upregulated and 377 downregulated. These results indicate that MeCP2 activates many genes, while repressing others. The study also found that MeCP2 binds to the promoters of six target genes, including Sst, Oprk1, Gamt, Gprin1, Mef2c, and A2bp1. MeCP2 interacts with CREB1 at activated promoters but not repressed ones, suggesting a role as an activator in certain contexts. The study also found that MeCP2 activates CREB1, which in turn represses MeCP2 translation, forming a negative regulatory loop. These findings resolve inconsistencies in the literature regarding MeCP2 and Bdnf, showing that MeCP2 activates Bdnf. The study highlights that MeCP2 functions as both an activator and repressor, with a greater role as an activator in the hypothalamus. The findings suggest that MeCP2 disorders are due to gain of function rather than loss of function, and that RTT is mainly due to loss of transcriptional activation. The study also suggests that therapeutic strategies should focus on restoring neuronal function rather than individual gene products. The results provide insight into the molecular mechanisms underlying MeCP2 disorders.MeCP2, a key contributor to neurological disease, activates and represses transcription. Mutations in the gene encoding MeCP2 cause Rett syndrome, a neurodevelopmental disorder. Loss of function or increased dosage of MeCP2 leads to various neuropsychiatric disorders. This study examined gene expression in the hypothalamus of mice with MeCP2 deficiency or overexpression. It found that MeCP2 dysfunction alters the expression of thousands of genes, with most (85%) being activated. MeCP2 binds to promoters of six genes and associates with CREB1 at activated targets but not repressed ones. These findings suggest MeCP2 functions as both an activator and repressor of transcription. MeCP2 is a transcriptional repressor that binds to methylated CpG dinucleotides and recruits corepressors. In mice, MeCP2 deficiency leads to neurological dysfunction, while overexpression causes similar symptoms to human MeCP2 duplication syndrome. The study used microarray analysis to compare gene expression in the hypothalamus of MeCP2-Tg and Mecp2-null mice, revealing that 2,184 genes were upregulated and 377 downregulated. These results indicate that MeCP2 activates many genes, while repressing others. The study also found that MeCP2 binds to the promoters of six target genes, including Sst, Oprk1, Gamt, Gprin1, Mef2c, and A2bp1. MeCP2 interacts with CREB1 at activated promoters but not repressed ones, suggesting a role as an activator in certain contexts. The study also found that MeCP2 activates CREB1, which in turn represses MeCP2 translation, forming a negative regulatory loop. These findings resolve inconsistencies in the literature regarding MeCP2 and Bdnf, showing that MeCP2 activates Bdnf. The study highlights that MeCP2 functions as both an activator and repressor, with a greater role as an activator in the hypothalamus. The findings suggest that MeCP2 disorders are due to gain of function rather than loss of function, and that RTT is mainly due to loss of transcriptional activation. The study also suggests that therapeutic strategies should focus on restoring neuronal function rather than individual gene products. The results provide insight into the molecular mechanisms underlying MeCP2 disorders.