Histone Demethylase KDM6B Promotes Postnatal Oligodendrocyte Development and Cortical Myelination

Myelination in the postnatal cortex requires epigenetic programs that activate oligodendrocyte gene networks. Here we show that the histone H3K27me3 demethylase KDM6B promotes this process <i>in vivo</i> . Conditional <i>Kdm6b</i> deletion ( <i>Kdm6b</i> -cKO) in Emx1 dorsal telencephalic progenitors caused delayed cortical myelination. Lineage-specific RNA-seq revealed that the oligodendrocyte master regulator <i>Sox10</i> was significantly reduced, as well as myelination effectors, indicating impaired oligodendrocyte maturation. Chromatin immunoprecipitation assays of the same lineage showed increased H3K27me3 at promoter-proximal regions of <i>Sox10,</i> consistent with loss of KDM6B-mediated de-repression. Temporally controlled <i>Sox10</i> induction partially rescued myelination in <i>Kdm6b</i> -cKO mice. These findings define a KDM6B→SOX10 axis that licenses oligodendrocyte development and cortical myelination by removing repressive H3K27me3 and sustaining active chromatin, with implications for KDM6B-related neurodevelopmental disorders.