GSE130858
The chromatic loci of H3.3K36M determine the preferential prevalence of K36M mutation at H3.3 in chondroblastomas
The histone H3.3K36M mutation, identified in over 90% of chondroblastoma cases, reprograms the H3K36 methylation landscape and gene expression to promote tumorigenesis. However, it's still unknown how the H3K36M mutation preferentially happens at the histone H3 variant H3.3. Here we report that, H3.3K36M mutation, but not H3.1K36M mutation, promoted increased colony formation and defects in differentiation. The reduction of H3K36 methylation and initiation of new H3K36 methylation sites in chromatin is dependent on the incorporation loci of H3.3K36M and H3.1K36M. Moreover, while both H3.3K36M and H3.1K36M mutation inactivated the enhancers, only H3.3K36M mutation changed the super enhancers associated with genes in general development, depending on the chromatic incorporation loci of H3.3K36M mutant proteins. Together, this study highlights the roles of the chromatic localization of H3.3K36M mutant proteins in the reprograming of epigenome and subsequent induction of tumorigenesis, and sheds light on the molecular mechanisms how H3K36M mutation mainly occurs at histone H3.3 in chondroblastomas. Overall design: To directly compare the different reprogramming of H3.3K36M and H3.1K36M on the epigenome and gene expression in cells.