Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape

Abstract

Several types of pediatric cancers reportedly contain high frequency missense mutations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized. Here, we report that the H3 lysine 36 to methionine (H3K36M) mutation impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in vivo. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy the H3K36M mutation. Following the loss of H3K36 methylation, a genome-wide gain in H3K27 methylation leads to a redistribution of Polycomb Repressive Complex 1 and de-repression of its target genes known to block mesenchymal differentiation. Our findings are mirrored in human undifferentiated sarcomas where novel K36M/I mutations in H3.1 are identified.

Histone Lysine-to-Methionine Mutations Reduce Histone Methylation and Cause Developmental Pleiotropy

“…To further determine the potency of the K36M as an inhibitor, we searched for the peptide signature of M36, based on its mass difference from K36, using mass spectrometry. Consistent with the low amount of K36M in tumors and cultured cells (Schwartzentruber et al, 2012;Behjati et al, 2013;Fang et al, 2016;Lu et al, 2016), we found that K36M peptides were present at an abundance of 1.4% among total detected H3.3 peptides (Supplemental Fig. S3A).…”

“…Given knowledge of K36M mutation inducing global reduction of H3K36 methylation in mammals (Lewis et al, 2013;Lu et al, 2016), we hypothesized that K36M may exert similar effects on the histone methylation landscape in plants. To test this hypothesis, we analyzed the accumulation level of various histone methylation marks in K36M by western blot.…”

“…Such K36M mutations were associated with 95% of chondroblastomas (Behjati et al, 2013). More recently, K36M mutation was shown to contribute to tumorigenesis by altering the expression of differentiation or cancer-related genes (Fang et al, 2016;Lu et al, 2016).…”

“…While K-to-M mutations promoting tumorigenesis have been investigated (Chan et al, 2013;Lewis et al, 2013;Fang et al, 2016;Lu et al, 2016), it is unknown whether K-to-M mutations influence organismal development. Using Arabidopsis as a model system, we report, to our knowledge, the first developmental phenotypic effects for the K36M mutation.…”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…For example, glycine 34 to tryptophan/leucine (G34W/L) mutations occur in giant cell tumors of the bone, lysine 36 to methionine (K36M) mutations have been reported in »95% of chondroblastomas, and H3K36 mutations promote sarcomagenesis. [39][40][41][42] Associated changes in DNA methylation patterns DNA methylation patterns have been extensively studied in adult GBM and have helped guide clinical trials, predicting the recurrence of tumors and resistance to radiotherapy. Indeed, CpG island methylator phenotype (G-CIMP) helped subdivide GBMs into glioma, G-CIMP-positive and G-CIMP-negative GBM subsets, partially predicting response to treatment.…”