Mecp2 acts as a key stabilizer of glucocorticoid-induced genes in active chromatin regions [scATAC-Seq]

Mutations in methyl-CpG-binding protein 2 (MECP2) constitute the primary cause of Rett syndrome (RTT). Although Mecp2 is ubiquitously expressed throughout the body, its functional profiling at the pan-tissue and multi-omics levels remains lacking. Here, we obtained transcriptomic and epigenomic profiles of various tissues from wild-type and RTT mice; revealed global hyperactivation of the glucocorticoid (GC)-induced genes (GIGs) following Mecp2 KO. Further analysis of the nervous system revealed that non-neuronal cells were more susceptible to abnormalities of the GC system, playing a crucial role in the neurological disturbances of RTT mice. Mechanistically, we found that MECP2 binds to the regulatory elements of active GIGs to suppress their hyperactivation; and competitively inhibits the binding between NR3C1 and NCOA1 to maintain GC system homeostasis. Our study dissects the critical functions of Mecp2 at the epigenomic, transcriptomic, and protein levels, providing new insights into the pathomechanisms of RTT.