Histone demethylase KDM6B promotes postnatal oligodendrocyte maturation and cortical myelination

Postnatal cortical myelination requires epigenetic activation of oligodendrocyte gene programs, but the role of histone demethylases in vivo remains unclear.

We conditionally deleted Kdm6b in Emx1⁺ dorsal telencephalic progenitors and analyzed oligodendrocyte lineage progression, performed lineage-specific RNA-seq, assessed H3K27me3 occupancy by chromatin immunoprecipitation, and tested functional rescue via Sox10 induction.

Kdm6b deletion delayed cortical myelination and impaired oligodendrocyte maturation without affecting precursor density. Pre-myelinating and mature oligodendrocyte markers were reduced. RNA-seq revealed early suppression of Sox10, followed by downregulation of myelin genes. Consistently, H3K27me3 enrichment increased at Sox10 regulatory regions. Sox10 induction partially rescued myelination deficits.

These findings define a KDM6B→SOX10 axis that promotes oligodendrocyte maturation and cortical myelination by restricting repressive H3K27me3, providing mechanistic insight into epigenetic control of myelination with relevance to KDM6B-associated neurodevelopmental disorders.