Mutations in Histone H3K36 Prevent Methylation and Drive Sarcomagenesis

The majority of chondroblastomas harbor a somatic missense mutation in histone H3 (H3K36M), but the oncogenic mechanisms are not well understood. These and other H3 mutations found in pediatric bone and brain tumors map at or near known sites of histone modifications, including methylation of H3K27 and H3K36, and exhibit a high degree of tumor-type specificity, indicating that the functional consequence of H3 mutations varies based on the tissue of origin. Lu and colleagues investigated the effects of H3K36M mutations in chondroblastoma, which is distinguished by hyperproliferation of immature chondroblast-like cells. Expression of wild-type or mutant (H3K36M) H3 in mouse mesenchymal progenitor cells (MPC) revealed that H3K36M promoted aberrant expression of genes involved in cellular differentiation, reduced the capacity for differentiation into chondrocytes, adipocytes, and osteocytes, and increased expression of transcription factors involved in mesenchymal multipotency. However, H3 mutations found in other tumor types did not affect chondrocytic differentiation, consistent with the tissue specificity of histone mutations in cancer. Further, H3K36M expression in MPCs was sufficient to induce undifferentiated sarcoma formation in vivo, and H3K36M and H3K36I mutations were identified in pediatric undifferentiated soft-tissue sarcomas. Impairment of chondrocyte differentiation by H3K36M/I correlated with reduced dimethylation and trimethylation of H3K36 (H3K36me2/3) and increased H3K27me2/3. Like H3K27 mutations in gliomas, which reduce H3K27 methylation by inhibiting the H3K27 methyltransferase polycomb repressive complex 2 (PRC2), H3K36M/I suppressed H3K36 methylation by inhibiting the activity of its cognate methyltransferases SETD2 and NSD2. The corresponding gain of H3K27me2/3 occurred mainly in intergenic regions and recruited PRC1 away from gene-associated regions, resulting in aberrant expression of differentiation genes normally repressed by PRC1. Together, these findings elucidate a role for H3K36 methylation in regulating H3K27 methylation and polycomb complex recruitment, and indicate that specific histone mutations are sufficient to promote sarcomagenesis by impairing MPC differentiation.

Lu C, Jain SU, Hoelper D, Bechet D, Molden RC, Ran L, et al. Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science 2016;352:844–9.

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