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MeCP2 stabilizes the glucocorticoid system in active chromatin regions [CUT&Tag]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE298418 | GEO | 2026/07/31

REPOSITORIES: GEO

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MeCP2 stabilizes the glucocorticoid system in active chromatin regions [RNA-seq]

Project description: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.

2026-07-31 | GSE295530 | GEO

Mecp2 stabilizes the glucocorticoid system in active chromatin regions [scRNA-Seq]

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