Oncohistones: a roadmap to stalled development

Abstract

Since the discovery of recurrent mutations in histone H3 variants in paediatric brain tumours, so-called 'oncohistones' have been identified in various cancers. While their mechanism of action remains under active investigation, several studies have shed light on how they promote genome-wide epigenetic perturbations. These findings converge on altered post-translational modifications on two key lysine (K) residues of the H3 tail, K27 and K36, which regulate several cellular processes, including those linked to cell differentiation during development. We will review how these oncohistones affect the methylation of cognate residues, but also disrupt the distribution of opposing chromatin marks, creating genome-wide epigenetic changes which participate in the oncogenic process. Ultimately, tumorigenesis is promoted through the maintenance of a progenitor state at the expense of differentiation in defined cellular and developmental contexts. As these epigenetic disruptions are reversible, improved understanding of oncohistone pathogenicity can result in needed alternative therapies.

Keywords: H3; development; differentiation; epigenome; oncohistones.

Figure 1.. Histone mutations in cancers

Schematic of the histone H3.3 tail above, highlighting key residues (K27, G34, K36) recurrently mutated in cancers and their associated post-translational modifications. Depicted below is the regional tissue specificity of oncohistone mutations and their occurrence in specific cancer types.

Figure 2.. Relationships between H3K27, H3K36 and DNA methylation

A. Methyltransferases performing the steps of de novo DNA methylation, H3K36 and H3K27 methylation. B. An example of repressed chromatin mediated by the PRC2 and PRC1 complexes, as initiated by PRC2 recruitment to unmethylated CpG islands (CGIs) and consequent spread of H3K27 methylation, and followed by chromatin compaction by canonical PRC1 which recognizes H3K27me3 through its CBX subunit. C. An example of active chromatin, illustrated by co-regulation of intergenic domains by H3K36me2- and H3K27ac-depositing enzymes, whereas genic deposition of H3K36me3 recruits various readers with distinct functions.

Figure 3.. Epigenetic mechanisms of oncohistone mutants

Schematic illustrating immediate consequences of oncohistone mutations on methyltransferase function (left), followed by downstream effects (right) resulting from disrupted boundaries and genomic redistribution of methyltransferases, or disruption of local reader recruitment.

Figure 4.. Intersection of oncohistone mutations with developmental lineages and oncogenic partner mutations

A. Oncohistone mutations occurring in high-grade gliomas follow a specific temporal and regional pattern with specific oncogenic partners, consistent with a distinct cell-of-origin. B. Murine models of H3.3 K27M using different techniques and in combination with oncogenic partner mutations, to achieve similarity with H3.3 K27M high-grade gliomas.