Mecp2 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.