GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE298nnn/GSE298418/primary200OKGenomicsMus musculusGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE298418GEOGSEfalseMeCP2 stabilizes the glucocorticoid system in active chromatin regions [CUT&Tag]Methyl-CpG-binding protein 2 (MeCP2), a key epigenetic factor regulating gene expression via DNA/chromatin interactions, causes Rett syndrome when dysfunctional. However, its regulatory mechanisms at the pan-tissue and multi-omics levels remain poorly understood. Here, we constructed comprehensive pan-tissue transcriptional profiles and chromatin accessibility profiles from wild-type and Mecp2-knockout mice. Integrative analyses revealed that glucocorticoid (GC)-induced genes (GIGs) exhibited global hyperactivation following Mecp2 knockout, highlighting a crucial role for MeCP2 in maintaining GC signaling homeostasis. Through innovative single-cell multi-omics profiling of the nervous system, we found that GIG dysregulation primarily disrupts neural homeostasis via non-neuronal cells. Mechanistically, we uncovered a dual regulatory mode of MeCP2: (1) competitively limiting NR3C1 occupancy at GIG cis-regulatory elements in active chromatin regions, and (2) specifically disrupting NR3C1-NCOA1 coactivator interactions. Importantly, pharmacologically suppressing aberrant GC system activation ameliorated pathological phenotypes and significantly prolonged survival in Mecp2-knockout mice. Our study demonstrates the critical pathological role of hyperactivated GC signaling in the multisystem disturbances of Mecp2-knockout mice and suggests potential therapeutic targets for Rett syndrome.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 musculus