Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants
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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 language | English |
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Journal | Cell Stem Cell |
Volume | 28 |
Issue number | 5 |
Pages (from-to) | 877-893.e9 |
ISSN | 1934-5909 |
DOIs | |
Publication status | Published - 2021 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:
© 2021 The Authors
- cancer, DIPG, forebrain, glioblastoma, histone H3.3, neural stem cells, neurodevelopment, pediatric high-grade glioma, ZMYND11
Research areas
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