Opposing Patterns of the Histone Variant MacroH2A1.1 in Fmr1 Knockout and BTBR T+ Itpr3tf/J Mouse Models of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) exhibits substantial heterogeneity, wherein genetic and idiopathic forms may converge on shared core phenotypes through divergent molecular pathways. The histone variant macroH2A1.1, implicated in chromatin repression and DNA repair, has been linked to behavioral alterations opposite to core ASD features when depleted systemically. However, its regional and cell-type-specific regulation in genetic versus idiopathic ASD models remains unclear. We investigated macroH2A1.1 expression across the dorsal striatum, hippocampus, and medial prefrontal cortex in Fmr1 knockout (Fragile X syndrome model) and BTBR T+ Itpr3tf/J (idiopathic ASD model) mice. Quantitative PCR and imaging analyses revealed opposing patterns: BTBR mice showed region-specific mRNA downregulation and increased strongly stained macroH2A1.1-positive nuclei, whereas Fmr1 knockout mice exhibited reduced strong staining with increased weak staining, specific to neurons and not astrocytes, independent of significant mRNA changes. Bulk RNA-seq meta-analysis and pseudobulk single-cell transcriptomics further identified pathway-level enrichment of oxidative phosphorylation, chromatin remodeling, and transcriptional repression functional gene sets in unmatched public datasets (BTBR striatum; FXS hippocampus and cortex), with pronounced neuron-astrocyte divergence in Fmr1 knockout cortex. These findings underscore distinct epigenetic regulatory mechanisms in genetic and idiopathic ASD models.