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MSL2 ORCHESTRATES OLIGODENDROCYTE PRECURSOR CELL CYCLE VIA H3K4ME3 TO PREVENT WHITE MATTER DEFECTS IN NEURODEVELOPMENTAL DISORDERS
Jie Yuanand 5 co-authors
Fourth Military Medical University
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS03-08AM-470
Presentation
Date TBA
Board: PS03-08AM-470
Event Information
Poster Board
PS03-08AM-470
Poster
View posterAbstract
Pathogenic variants in MSL2, a core component of the histone-modifying MSL complex, are associated with neurodevelopmental disorders (NDDs) and white matter abnormalities (WMA), though their pathogenic mechanisms remain unknown. In this study, we identified three NDD patients carrying MSL2 variants, all exhibiting WMA. Using conditional knockout mice, we demonstrated that oligodendrocyte-lineage-specific deletion of
Msl2 disrupts OPC 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, while its loss aberrantly activates immune-related pathways. Furthermore, cell synchronization study confirmed that MSL2 is required for metaphase spindle formation in OPCs, providing a mechanistic basis for the 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.
Msl2 disrupts OPC 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, while its loss aberrantly activates immune-related pathways. Furthermore, cell synchronization study confirmed that MSL2 is required for metaphase spindle formation in OPCs, providing a mechanistic basis for the 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.
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