MSL2 orchestrates oligodendrocyte precursor cell cycle via H3K4me3 to prevent white matter defects in neurodevelopmental disorders.

Pathogenic variants in MSL2, a core component of the histone-modifying MSL complex, are associated with neurodevelopmental disorders (NDDs) and white matter abnormalities; however, their mechanisms of pathogenicity remain unknown. In this study, we identified three patients with NDD carrying MSL2 variants, all of whom exhibited white matter abnormalities. Using conditional knockout mice, we demonstrated that oligodendrocyte lineage-specific deletion of Msl2 disrupts oligodendrocyte precursor cell proliferation, maturation, and myelination in a cell-autonomous manner, leading to autism-like behaviors including social deficits and repetitive behaviors. Integrated transcriptomic and epigenomic profiling revealed that MSL2 maintains H3K4me3 occupancy at promoters of genes essential for cell cycle progression, mitotic spindle assembly, and myelination, whereas its loss aberrantly activates immune-related pathways. Furthermore, a cell synchronization study confirmed that MSL2 is required for metaphase spindle formation in oligodendrocyte precursor cells, providing a mechanistic basis for impaired oligodendroglial development and hypomyelination. Our findings establish MSL2 as a critical epigenetic regulator of oligodendrocyte lineage progression and propose MSL2-targeted interventions as a promising therapeutic strategy for NDD-related white matter defects.