The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas

ABSTRACT: Over 90% of chondroblastomas contain a heterozygous mutation replacing lysine 36 with methionine (K36M) in the histone H3 variant H3.3. The role of the H3.3K36M mutation in tumorigenesis of this typically benign bone tumor with high recurrence rates is unknown. Here, we show that H3K36 di- and tri-methylation (me2 and me3) levels are reduced globally in chondroblastomas, as well as in chondrocytes stably expressing the H3.3K36M mutation because the H3.3M36 mutation protein inhibits the activity of lysine methyl transferases, MMSET and SetD2. Remarkably, at gene bodies, H3K36me2 increases and H3K36me3 decreases, which correlates with elevated and reduced expression of the underlying genes, respectively. Genes with altered H3K36me2/me3 and gene expression are associated with cancer pathways and chondrocyte differentiation. Chondrocytes harboring the H3.3K36M mutation exhibit cancer-associated cellular phenotypes and delayed chondrocyte differentiation associated with reduced Bmp2 and Runx2 expression. Exogenous Bmp2 partially rescued the delays in chondrocyte differentiation. Thus, H3.3K36M mutant proteins dominantly reprogram H3K36me2/me3 and chondrocyte gene expression, inhibiting terminal chondrocyte differentiation and contributing to tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE75234 | GEO | 2016/10/06

SECONDARY ACCESSION(S): PRJNA302855

REPOSITORIES: GEO