MSL2 orchestrates oligodendrocyte precursor cell cycle via H3K4me3 to prevent white matter defects in neurodevelopmental disorders
9 affiliations
- 1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi China
- 2The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi’an, Shaanxi China
- 3Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha, Hunan China
- 4Department of Medical Genetics, The Affiliated Children’s Hospital of Xiangya School of Medicine (Hunan Children’s Hospital), Central South University, Changsha, Hunan China
- 5Genetica AG, Human Genetics and Genetic Counselling Unit, Zurich, Switzerland
- 6Hunter Genetics, Waratah, NSW Australia
- 7School of Medicine and Public Health, University of Newcastle, Callaghan, NSW Australia
- 8Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC Australia
- 9Department of Paediatrics, University of Melbourne, Melbourne, VIC Australia
Abstract
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.
Related
- Oligodendrocyte precursor cell death does not contribute to lifelong population homeostasis
- SET Domain Genes in Neurodevelopmental Disorders
- Neurodevelopmental disorders in infants treated with anti-VEGF agents vs. laser photocoagulation or cryotherapy for ROP
- Parsing altered brain connectivity in neurodevelopmental disorders by integrating graph-based normative modeling and deep generative networks
- Copy number variants (CNVs) interfere with human accelerated regions (HARs) in neurodevelopmental disorders: a large-scale cohort study
BibTeX
@article{yuan2026msl2,
title = {{MSL2 orchestrates oligodendrocyte precursor cell cycle via H3K4me3 to prevent white matter defects in neurodevelopmental disorders}},
author = {Jie Yuan and Yuhao Dong and Kaixiang Zhang and Zhongcheng Wei and Zhongzhe Zhang and Ming Zhang and Shengjie Luo and Sufang Jiang and Yu Peng and Xinghan Wu and Herenger Yvan and Himanshu Goel and Elaine Zhang and The Australian Undiagnosed Diseases Network (UDN-Aus) and Hui Guo and Shengxi Wu and Xianghui Zhao},
journal = {Experimental \& Molecular Medicine},
year = {2026},
month = oct,
doi = {10.1038/s12276-026-01858-1},
url = {https://doi.org/10.1038/s12276-026-01858-1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - MSL2 orchestrates oligodendrocyte precursor cell cycle via H3K4me3 to prevent white matter defects in neurodevelopmental disorders
AU - Jie Yuan
AU - Yuhao Dong
AU - Kaixiang Zhang
AU - Zhongcheng Wei
AU - Zhongzhe Zhang
AU - Ming Zhang
AU - Shengjie Luo
AU - Sufang Jiang
AU - Yu Peng
AU - Xinghan Wu
AU - Herenger Yvan
AU - Himanshu Goel
AU - Elaine Zhang
AU - The Australian Undiagnosed Diseases Network (UDN-Aus)
AU - Hui Guo
AU - Shengxi Wu
AU - Xianghui Zhao
PY - 2026
DA - 2026/10/06
JO - Experimental & Molecular Medicine
DO - 10.1038/s12276-026-01858-1
UR - https://doi.org/10.1038/s12276-026-01858-1
AB - 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.
SN - 1226-3613
SN - 2092-6413
ER -