Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression
Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel la présence d'une mutation G34 au niveau de l'histone H3.3, en favorisant l'activité du complexe protéique PRC2, induit la progression tumorale
A high frequency of missense mutations was recently discovered at histone H3.3 glycine 34 in 92% of giant cell tumors of the bone and 17% of high-grade astrocytomas. The molecular mechanism by which G34 mutations drive these tumors remains unclear. Here, we demonstrate that the G34-mutated “oncohistones” misregulate the negative cross-talk between two histone methyltransferase enzymes, Polycomb Repressive Complex 2 (PRC2) and SETD2. G34 mutations uniquely promote PRC2 activity by blocking SETD2-mediated H3K36 methylation at active enhancers and drive a gene expression program that enhances tumor growth. We propose that G34 oncohistones exploit the regulatory mechanisms that fine tune PRC2 activity in human malignancies.A high percentage of pediatric gliomas and bone tumors reportedly harbor missense mutations at glycine 34 in genes encoding histone variant H3.3. We find that these H3.3 G34 mutations directly alter the enhancer chromatin landscape of mesenchymal stem cells by impeding methylation at lysine 36 on histone H3 (H3K36) by SETD2, but not by the NSD1/2 enzymes. The reduction of H3K36 methylation by G34 mutations promotes an aberrant gain of PRC2-mediated H3K27me2/3 and loss of H3K27ac at active enhancers containing SETD2 activity. This altered histone modification profile promotes a unique gene expression profile that supports enhanced tumor development in vivo. Our findings are mirrored in G34W-containing giant cell tumors of bone where patient-derived stromal cells exhibit gene expression profiles associated with early osteoblastic differentiation. Overall, we demonstrate that H3.3 G34 oncohistones selectively promote PRC2 activity by interfering with SETD2-mediated H3K36 methylation. We propose that PRC2-mediated silencing of enhancers involved in cell differentiation represents a potential mechanism by which H3.3 G34 mutations drive these tumors.The next-generation sequencing data generated in this study are deposited at GEO database with accession nos. GSE133722 (54) and GSE118785 (55). Published data used in this paper were downloaded from GEO (accession no. GSE103559) (56).