GE-08: IMPACT OF H3.3K27M MUTATION ON CANCER EPIGENOME

Diffuse intrinsic pontine glioma (DIPG) is an aggressive primary brain tumor found exclusively in children and the median survival for DIPG patients is about one year from diagnosis. Recent studies have uncovered that a somatic mutation in the H3F3A gene, which has been observed in 80% of DIPG cases, is likely a main driver of tumorigenesis. H3F3A encodes histone H3 variant H3.3 that plays an important role in regulating gene expression during development. The predominant mutation at H3F3A leads to amino acid change at lysine (K) 27 residue of H3.3 to methionine (M). In human cells, there are two genes that encode H3.3 and 14 genes that encode histones H3.1 and H3.2. H3.3 differs from H3.1 and H3.2 by four or five amino acids. Lysine 27 is conserved among all these histone H3 proteins. Therefore, it is unknown how H3.3K27M mutation, which occurs at one allele of H3F3A gene, promotes tumorigenesis. We and others have shown that a global loss of H3K27 methylation occurs in DIPG cells with a K27M mutation. H3K27 methylation is catalyzed by the PRC2 lysine methyltransferase and plays an important role in gene silencing during stem cell differentiation and maintenance. We also observed that in addition to the global loss of H3K27me3 which is associated with gene activation, H3K27me3 is still present at the gene promoters of about 800 genes. These genes are enriched in cancer pathways. At this meeting, I will present our recent findings indicating why some gene loci are enriched with H3K27me3 in H3.3K27M mutant tumor lines.