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

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Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants. / Bressan, Raul Bardini; Southgate, Benjamin; Ferguson, Kirsty M.; Blin, Carla; Grant, Vivien; Alfazema, Neza; Wills, Jimi C.; Marques-Torrejon, Maria Angeles; Morrison, Gillian M.; Ashmore, James; Robertson, Faye; Williams, Charles A.C.; Bradley, Leanne; von Kriegsheim, Alex; Anderson, Richard A.; Tomlinson, Simon R.; Pollard, Steven M.

In: Cell Stem Cell, Vol. 28, No. 5, 2021, p. 877-893.e9.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Bressan, RB, Southgate, B, Ferguson, KM, Blin, C, Grant, V, Alfazema, N, Wills, JC, Marques-Torrejon, MA, Morrison, GM, Ashmore, J, Robertson, F, Williams, CAC, Bradley, L, von Kriegsheim, A, Anderson, RA, Tomlinson, SR & Pollard, SM 2021, 'Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants', Cell Stem Cell, vol. 28, no. 5, pp. 877-893.e9. https://doi.org/10.1016/j.stem.2021.01.016

APA

Bressan, R. B., Southgate, B., Ferguson, K. M., Blin, C., Grant, V., Alfazema, N., Wills, J. C., Marques-Torrejon, M. A., Morrison, G. M., Ashmore, J., Robertson, F., Williams, C. A. C., Bradley, L., von Kriegsheim, A., Anderson, R. A., Tomlinson, S. R., & Pollard, S. M. (2021). Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants. Cell Stem Cell, 28(5), 877-893.e9. https://doi.org/10.1016/j.stem.2021.01.016

Vancouver

Bressan RB, Southgate B, Ferguson KM, Blin C, Grant V, Alfazema N et al. Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants. Cell Stem Cell. 2021;28(5):877-893.e9. https://doi.org/10.1016/j.stem.2021.01.016

Author

Bressan, Raul Bardini ; Southgate, Benjamin ; Ferguson, Kirsty M. ; Blin, Carla ; Grant, Vivien ; Alfazema, Neza ; Wills, Jimi C. ; Marques-Torrejon, Maria Angeles ; Morrison, Gillian M. ; Ashmore, James ; Robertson, Faye ; Williams, Charles A.C. ; Bradley, Leanne ; von Kriegsheim, Alex ; Anderson, Richard A. ; Tomlinson, Simon R. ; Pollard, Steven M. / Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants. In: Cell Stem Cell. 2021 ; Vol. 28, No. 5. pp. 877-893.e9.

Bibtex

@article{c79b770f82b24ac2a5c60e3a5f1888b2,
title = "Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants",
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.",
keywords = "cancer, DIPG, forebrain, glioblastoma, histone H3.3, neural stem cells, neurodevelopment, pediatric high-grade glioma, ZMYND11",
author = "Bressan, {Raul Bardini} and Benjamin Southgate and Ferguson, {Kirsty M.} and Carla Blin and Vivien Grant and Neza Alfazema and Wills, {Jimi C.} and Marques-Torrejon, {Maria Angeles} and Morrison, {Gillian M.} and James Ashmore and Faye Robertson and Williams, {Charles A.C.} and Leanne Bradley and {von Kriegsheim}, Alex and Anderson, {Richard A.} and Tomlinson, {Simon R.} and Pollard, {Steven M.}",
note = "Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
doi = "10.1016/j.stem.2021.01.016",
language = "English",
volume = "28",
pages = "877--893.e9",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "5",

}

RIS

TY - JOUR

T1 - Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants

AU - Bressan, Raul Bardini

AU - Southgate, Benjamin

AU - Ferguson, Kirsty M.

AU - Blin, Carla

AU - Grant, Vivien

AU - Alfazema, Neza

AU - Wills, Jimi C.

AU - Marques-Torrejon, Maria Angeles

AU - Morrison, Gillian M.

AU - Ashmore, James

AU - Robertson, Faye

AU - Williams, Charles A.C.

AU - Bradley, Leanne

AU - von Kriegsheim, Alex

AU - Anderson, Richard A.

AU - Tomlinson, Simon R.

AU - Pollard, Steven M.

N1 - Publisher Copyright: © 2021 The Authors

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - cancer

KW - DIPG

KW - forebrain

KW - glioblastoma

KW - histone H3.3

KW - neural stem cells

KW - neurodevelopment

KW - pediatric high-grade glioma

KW - ZMYND11

UR - http://www.scopus.com/inward/record.url?scp=85103260742&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2021.01.016

DO - 10.1016/j.stem.2021.01.016

M3 - Journal article

C2 - 33631116

AN - SCOPUS:85103260742

VL - 28

SP - 877-893.e9

JO - Cell Stem Cell

JF - Cell Stem Cell

SN - 1934-5909

IS - 5

ER -

ID: 271622493