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

Hsiao P.J. Voon, Maheshi Udugama, Wendi Lin, Linda Hii, Ruby H.P. Law, David L. Steer, Partha P. Das, Jeffrey R. Mann, Lee H. Wong

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Article number3142
Number of pages10
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018

Keywords

  • histone post-translational modifications
  • histone variants

Cite this

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

In: Nature Communications, Vol. 9, No. 1, 3142, 01.12.2018.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Voon, Hsiao P.J.

AU - Udugama, Maheshi

AU - Lin, Wendi

AU - Hii, Linda

AU - Law, Ruby H.P.

AU - Steer, David L.

AU - Das, Partha P.

AU - Mann, Jeffrey R.

AU - Wong, Lee H.

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AB - 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.

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