Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants

Raul Bardini Bressan, Benjamin Southgate, Kirsty M Ferguson, Carla Blin, Vivien Grant, Neza Alfazema, Jimi C Wills, Maria Angeles Marques, Gillian M Morrison, James Ashmore, Faye Robertson, Charles A C Williams, Leanne Bradley, Alex von Kriegsheim, Richard A Anderson, Simon R Tomlinson, Steven M Pollard

Research output: Contribution to journalArticlepeer-review

Abstract

Point mutations within the histone H3.3 are frequent in aggressive childhood brain tumors known as pediatric high-grade gliomas (pHGGs). Intriguingly, distinct mutations arise in discrete anatomical regions: H3.3-G34R within the forebrain and H3.3-K27M preferentially within the hindbrain. The reasons for this contrasting etiology are unknown. By engineering human fetal neural stem cell cultures from distinct brain regions, we demonstrate here that cell-intrinsic regional identity provides differential responsiveness to each mutant that mirrors the origins of pHGGs. Focusing on H3.3-G34R, we find that the oncohistone supports proliferation of forebrain cells while inducing a cytostatic response in the hindbrain. Mechanistically, H3.3-G34R does not impose widespread transcriptional or epigenetic changes but instead impairs recruitment of ZMYND11, a transcriptional repressor of highly expressed genes. We therefore propose that H3.3-G34R promotes tumorigenesis by focally stabilizing the expression of key progenitor genes, thereby locking initiating forebrain cells into their pre-existing immature state.

Original languageEnglish
JournalCell Stem Cell
DOIs
Publication statusPublished - 24 Feb 2021

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