Abstract
An array of oncogenic histone point mutations have been identified across a number of different cancer studies. It has been suggested that some of these mutant histones can exert their effects by inhibiting epigenetic writers. Here, we report that the H3.3 G34R (glycine to arginine) substitution mutation, found in paediatric gliomas, causes widespread changes in H3K9me3 and H3K36me3 by interfering with the KDM4 family of K9/K36 demethylases. Expression of a targeted single-copy of H3.3 G34R at endogenous levels induced chromatin alterations that were comparable to a KDM4 A/B/C triple-knockout. We find that H3.3 G34R preferentially binds KDM4 while simultaneously inhibiting its enzymatic activity, demonstrating that histone mutations can act through inhibition of epigenetic erasers. These results suggest that histone point mutations can exert their effects through interactions with a range of epigenetic readers, writers and erasers.
Highlights
An array of oncogenic histone point mutations have been identified across a number of different cancer studies
We find that this mutation triggers a gain in H3K36me[3] across the genome, suggesting that H3.3 G34R inhibits the activity of a histone lysine demethylase
Transcriptional changes for a number of genes were confirmed by qRT-PCR (Supplementary Fig. 3e). These results demonstrate that expression of a single copy of H3.3 G34R is sufficient to trigger chromatin and transcriptional changes which are highly similar to those observed in KDM4-tKO mutants, strongly suggesting that this is a major pathway through which H3.3 G34R exerts its effects
Summary
An array of oncogenic histone point mutations have been identified across a number of different cancer studies. Examples include the H3/H3.3 K27M mutation which is frequently detected in paediatric gliomas[22,23], and H3/H3.3 K36M mutations which are common in chondroblastomas[24] and head and neck squamous cell carcinomas[25] These lysine to methionine mutations have been demonstrated to act in a dominant-negative manner by inhibiting the histone lysine methyltransferases which normally methylate the cognate residues, resulting in genome-wide chromatin alterations[26,27]. We created a single-copy H3f3a G34R targeted mutation in mouse embryonic stem (ES) cells to faithfully recapitulate the mutations identified in paediatric gliomas We find that this mutation triggers a gain in H3K36me[3] across the genome, suggesting that H3.3 G34R inhibits the activity of a histone lysine demethylase. The IDH1/2 mutations are known to inhibit the KDM4 demethylases, raising the possibility that H3.3 G34R and IDH1/2 mutations may drive oncogenesis through parallel pathways
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
