Inhibition of a K9/K36 demethylase by an H3.3 point mutation found in paediatric glioblastoma

• Published in: Nature communications Vol. 9; no. 1; pp. 3142 - 10
• Main Authors: Voon, Hsiao P. J., Udugama, Maheshi, Lin, Wendi, Hii, Linda, Law, Ruby H.P., Steer, David L., Das, Partha P., Mann, Jeffrey R., Wong, Lee H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.08.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 14/1; 38/23; 38/39; 38/77; 38/91; 42/109; 45/29; 49/15; 49/88; 631/337/100/2285; 631/337/100/2286; 96/106; Amino acid substitution; Animals; Arginine; Arginine - chemistry; Biotinylation; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Cancer; Child; Chromatin; Chromatin - chemistry; Disease Models, Animal; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Enzymatic activity; Epigenesis, Genetic; Epigenetics; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glycine; Glycine - chemistry; Histones; Histones - genetics; Histones - metabolism; Humanities and Social Sciences; Humans; Kinases; Mice; multidisciplinary; Mutation; Point Mutation; Protein Binding; Science; Science (multidisciplinary); Sequence Analysis, RNA; Transgenes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05607-5

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. Recent studies have identified a number of oncogenic histone point mutations in different cancers. Here the authors provide evidence that H3.3 G34R substitution mutation, which is found in paediatric gliomas, causes changes in H3K9me3 and H3K36me3 by interfering with the KDM4 family of K9/K36 demethylases.