Ezh2 variant orchestrates cholesterol biosynthesis via epigenetic regulation in mouse cerebellum
Abstract
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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