Histone H3 Lysine 27 Mutations Block Methylation

Highly recurrent mutations in H3F3A, which encodes the histone H3 variant H3.3, and HIST1H3B, which encodes the histone H3 variant H3.1, have recently been identified in pediatric gliomas. Remarkably, these mutations invariably occur at or near sites of key regulatory posttranslational modifications, namely Lys27 and Gly34, suggesting that these cancers may be driven by altered epigenetic states. Lewis and colleagues analyzed global levels of regulatory histone modifications in diffuse intrinsic pontine glioma (DIPG) samples with H3.1 or H3.3 Lys27Met (K27M) mutations and specifically found decreased levels of H3K27 trimethylation (H3K27me3) and increased H3K27 acetylation compared with non-K27M mutant DIPGs. The finding that H3K27me3 was globally reduced despite the low contribution of mutant histone variants to total cellular histone H3 levels indicated that K27M expression reduces methylation on wild-type H3 histones. Indeed, nucleosomes purified from K27M-expressing cells had markedly lower amounts of H3K27me3 on endogenous H3. Interestingly, these changes were specifically induced by histones with K27M mutations, as expression of histones with other amino acid substitutions at K27 had no effect on H3K27me3 levels. Consistent with these findings, K27M peptides specifically reduced H3 trimethylation by Polycomb repressive complex 2 (PRC2) in a dose-dependent manner by interacting with the active site of EZH2, the SET domain methyltransferase subunit of PRC2. H3.3 K9M and K36M mutations likewise decreased overall H3K9me3 and H3K36me3 levels in association with SET domain histone methyltransferase inhibition, suggesting that this class of mutations may represent a general mechanism by which epigenetic states can be altered and raising the possibility that additional pathologic histone mutations may remain to be identified.

Lewis PW, Müller MM, Koletsky MS, Cordero F, Lin S, Banaszynski LA, et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 2013 Mar 28 [Epub ahead of print].