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

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

Cell stem cell (2021-02-26)
Raul Bardini Bressan, Benjamin Southgate, Kirsty M Ferguson, Carla Blin, Vivien Grant, Neza Alfazema, Jimi C Wills, Maria Angeles Marques-Torrejon, 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
摘要

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.

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Millipore
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cOmplete Mini蛋白酶抑制剂Cocktail, Tablets provided in a glass vial
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衰老细胞组织化学染色试剂盒, sufficient for 100 tests
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