GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE299nnn/GSE299346/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE299346GEOGSEfalseMecp2 stabilizes the glucocorticoid system in active chromatin regions [scRNA-Seq]Methyl-CpG-binding protein 2 (MECP2), a key epigenetic factor regulating gene expression via DNA/chromatin interactions, causes multisystem disorders when dysfunctional. However, its epigenetic regulatory mechanisms at the pan-tissue and multi-omics levels remain poorly understood. Here, we established comprehensive pan-tissue expression profiles in wild-type and Mecp2-knockout mice, revealing a crucial role for MECP2 in maintaining glucocorticoid (GC) signaling homeostasis. Single-cell epigenomic analyses demonstrated widespread increases in chromatin accessibility at GC-induced genes (GIGs) upon Mecp2 deficiency. Through innovative single-cell multi-omics profiling of the nervous system, we further revealed that GIG dysregulation primarily disrupts neural homeostasis via non-neuronal cells. Mechanistically, we identified a dual regulatory mode of MECP2: (1) competitively inhibiting NR3C1 binding to the cis-regulatory elements of GIGs in active chromatin regions, and (2) specifically disrupting NR3C1-NCOA1 coactivator interactions. These findings not only elucidate a novel MECP2-NR3C1-NCOA1 axis in GC system regulation but also suggest potential therapeutic targets for Rett syndrome.2026/07/31GSE299346GSM9037702GSM9037701GSM9037704GSM9037703GSM9037687GSM9037686GSM9037689GSM9037700GSM9037688GSM9037683GSM9037682GSM9037685GSM9037684GSM9037681GSM9037680GSM9037679GSM9037698GSM9037676GSM9037697GSM9037678GSM9037711GSM9037699GSM9037710GSM9037677GSM9037694GSM9037693GSM9037696GSM9037695GSM9037690GSM9037692GSM9037691GSM9037709GSM9037706GSM9037705GSM9037708GSM903770728330299346Mus musculus