Oncogenic Mechanisms of Histone H3 Mutations

Abstract

Recurrent missense mutations in histone H3 were recently reported in pediatric gliomas and soft tissue tumors. Strikingly, these mutations only affected a minority of the total cellular H3 proteins and occurred at or near lysine residues at positions 27 and 36 on the amino-terminal tail of H3 that are subject to well-characterized posttranslational modifications. Here we review recent progress in elucidating the mechanisms by which these mutations perturb the chromatin landscape in cells through their effects on chromatin-modifying machinery, particularly through inhibition of specific histone lysine methyltransferases. One common feature of histone mutations is their ability to arrest cells in a primitive state refractory to differentiation induction, highlighting the importance of studying these mutations in their proper developmental context.

Figure 1.

Posttranslational modification of the histone variant H3.3 and its chaperone/deposition machinery. (A) The amino-terminal tail of histone H3.3 (shown here) and other histone H3 proteins are subject to methylation of lysine residue 27 by the Polycomb repressive complex 2 (PRC2), containing core subunits EED, SUZ12, and EZH2. Removal of H3K27 methylation is performed by KDM6 family demethylases, including JMJD3 and UTX. Lysine residue 36 is subject to methylation by multiple enzymes, including the NSD family enzymes and SETD2. Removal of H3K36 methylation is performed by the KDM2 and KDM4 family demethylases. (B) Histone variant H3.3 is deposited at pericentric heterochromatin, telomeres, and certain endogenous retroviral elements (ERV) by the ATRX/DAXX heterodimeric complex. In contrast, H3.3 is deposited at euchromatin regions such as promoters and gene bodies by the histone chaperone HIRA (see Banaszynski et al. 2010 and Maze et al. 2014 for details and references).

Figure 2.

Recurrent histone mutations in human cancer (see text and Fontebasso et al. 2014a; Kallappagoudar et al. 2015). pHGG, Pediatric high-grade glioma; GCT, giant cell tumor.

Figure 3.

Inhibition of histone lysine methyltransferases (HMTs) by histone H3 oncohistone mutations. (A) Unimpeded activity of HMTs in the absence of a mutation (wild-type). (B) H3K9M, H3K27M, and H3K36M mutations dominantly inhibit their respective HMTs in trans. Consequently, nonmutant nucleosomes are hypomethylated (global methylation loss). (C) H3G34 mutations inhibit H3K36 HMTs in cis such that only nucleosomes containing the mutation are unable to be methylated (localized methylation loss).