Cell autonomous regional differences in oligodendrocyte precursor cell development and response to oncohistone H3.3 K27M [ATAC-Seq]

Diffuse midline glioma (DMG) is an incurable tumor arising in brainstem and midline structures. Most DMGs harbor missense histone H3 mutations replacing lysine 27 with methionine (H3 K27M). The mechanisms underlying regional selectivity for H3 K27M mutations, which are found almost exclusively in DMG, are not well understood. Here, we use a conditional knock-in mouse model to probe the postnatal brain region-specific oncogenic effects of H3.3 K27M in embryonic GFAP+ neural stem cells. We show that H3.3 K27M reduces oligodendrocyte differentiation in a region-specific manner and increases postnatal proliferation of distinct progenitor states by brain region in vivo, selectively expanding the oligodendrocyte-lineage in the ventral pons. Cellular morphology, marker expression, and transcriptomic analyses of primary region-specific mouse OPC cultures demonstrated cell-intrinsic differences in wild-type brainstem and forebrain OPC differentiation dynamics. H3.3 K27M drives cell-autonomous increase in brainstem-derived OPC proliferation and disrupts intrinsic region-specific transcriptional programs, delaying differentiation in forebrain-derived OPCs and restraining full maturation of brainstem-derived OPCs. H3.3 K27M-mediated changes include brainstem-selective upregulation of genes in Bmp, Wnt, and Notch pathways that are relevant in DMG pathogenesis. Our findings reveal that H3.3 K27M differentially disrupts cell-autonomous regional oligodendrocyte development, which may provide an opportunistic window for brainstem-selective gliomagenesis.