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Ezh2 variant orchestrates cholesterol biosynthesis via epigenetic regulation in mouse cerebellum

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作者

    Fei Guan， 
    Fei Guan
    • Huazhong University of Science and Technology, Tongji Medical College School of Basic Medicine
    Zongyan Jiang， 
    Zongyan Jiang
    • Huazhong University of Science and Technology, Tongji Medical College School of Basic Medicine
    Ye Tian， 
    Ye Tian
    • Huazhong University of Science and Technology, Tongji Medical College School of Basic Medicine
    Bijun Jiang， 
    Bijun Jiang
    • Huazhong University of Science and Technology, Tongji Medical College School of Basic Medicine
    Yixian Fan， 
    Yixian Fan
    • Huazhong University of Science and Technology, Tongji Medical College School of Basic Medicine
    Huamin Liang， 
    Huamin Liang
    • Huazhong University of Science and Technology, Tongji Medical College School of Basic Medicine
    Jing Jin， 
    Jing Jin
    • Huazhong University of Science and Technology, Tongji Medical College School of Basic Medicine
    Ying Yin， 
    Ying Yin
    • Huazhong University of Science and Technology, Tongji Medical College School of Basic Medicine
    Ximiao He
    Ximiao He
    • Huazhong University of Science and Technology, Tongji Medical College School of Basic Medicine
分类
神经生物学
关键词
cerebellum; Ezh2; alternative splicing; multi-omics; epigenetics; cholesterol; astroglia

摘要

Alternative splicing is highly prevalent and evolutionarily conserved in the brain, contributing to neuronal diversity and function. The chromatin modifier enhancer of zeste homolog 2 (EZH2) undergoes extensive splicing, but the functional significance of exon 3 donor site selection in the adult brain remains unclear. In this study, we identify the exon 3 long isoform of Ezh2 (Ezh2Long) as a cerebellum-enriched isoform with an important role in neurological function. Loss of Ezh2Long reduces the expression of cholesterol biosynthesis genes and lowers cerebellar cholesterol levels, in association with increased H3K27me3-mediated repression at SREBP2-targeted promoters. Ezh2Long deficiency disrupts astroglial cholesterol homeostasis and myelination, accompanied by neurological abnormalities. Notably, cholesterol restoration via valproic acid (VPA) treatment ameliorates myelination and behavioral deficits in Ezh2Long-/- mice. In summary, our findings identify Ezh2Long as a critical regulator of cerebellar cholesterol metabolism and highlight the importance of Ezh2 alternative splicing in maintaining cerebellar homeostasis and neurological function.

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DOI：

https://doi.org/10.65215/LTSpreprints.2026.09.24.000353

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353

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2026-09-25

如何引用

Guan, F., Jiang, Z., Tian, Y., Jiang, B., Fan, Y., Liang, H., Jin, J., Yin, Y., & He, X. (2026). Ezh2 variant orchestrates cholesterol biosynthesis via epigenetic regulation in mouse cerebellum. 浪淘沙预印本平台. https://doi.org/10.65215/LTSpreprints.2026.09.24.000353

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