UCSF

Greater than 60% of cases of diffuse intrinsic pontine glioma (DIPG) – a malignant pediatric brain tumor – carry a point mutation in the histone 3.3 gene that changes lysine 27 to methionine (K27M). The H3.3K27M mutant histone protein is a driver of DIPG and inhibits Polycomb Repressive Complex 2 (PRC2), resulting in global loss of histone 3 lysine trimethylation (H3K27me3) – a transcriptionally repressive chromatin modification – but the loss of H3K27me3 does not strongly correspond to gene de-repression in DIPG. Thus, how H3.3K27M drives oncogenic gene expression in DIPG remains poorly understood. Here, we investigate lamina-associated domains (LADs), chromatin regions near the nuclear periphery, and their reorganization in H3.3K27M-expressing cells. Using Genome Organization using CUT&RUN (GO-CaRT) and RNA-Seq analyses across DIPG cell lines, primary tumor nuclei, and embryonic stem cell models, we demonstrate that H3.3K27M selectively disrupts facultative LADs—regions critical for cell-type-specific gene regulation. Lost LADs exhibit a mix of repressive and activating histone marks and elevated expression of neuronal genes, linked to DIPG tumorigenesis. Our findings identify LAD remodeling as a key pathway to enable oncogenic transcriptional programs in H3.3K27M-driven glioma.