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-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*

*Corresponding author af dette arbejde

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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.

OriginalsprogEngelsk
TidsskriftCell Stem Cell
Vol/bind28
Udgave nummer5
Sider (fra-til)877-893.e9
ISSN1934-5909
DOI
StatusUdgivet - 2021
Udgivet eksterntJa

Bibliografisk note

Funding Information:
We thank Adrian P. Bracken, Katrin Ottersbach, Kim B. Jensen, and members of the Pollard lab for helpful discussions and critical reading of the manuscript. Abdenour Soufi provided technical advice on ChIP-seq protocols, and Angel Montero Carcaboso generously provided the patient-derived cell line pGBM002 (HSJD-GBM-002). We are grateful to the University College London Cancer Institute Genomics core facility for performing the next-generation mRNA sequencing and to the Wellcome Trust for providing the mass spectrometry large equipment (Multiuser Equipment Grant 208402/Z/17/Z ). Primary fetal NSCs were provided by the Glioma Cellular Genetics Resource ( www.gcgr.org.uk ). The project was supported by a grant from the Children with Cancer UK Charity ( 15/189 ). R.B.B. was supported by a PhD fellowship from the Science Without Borders Program (CAPES, Governo Dilma Rousseff, Brazil) and a postdoctoral fellowship from the European Molecular Biology Organization (EMBO). G.M.M. was supported by the Cancer Research UK Centre Accelerator Award ( A21922 ). S.M.P is a Cancer Research UK Senior Research Fellow ( A17368 ).

Funding Information:
We thank Adrian P. Bracken, Katrin Ottersbach, Kim B. Jensen, and members of the Pollard lab for helpful discussions and critical reading of the manuscript. Abdenour Soufi provided technical advice on ChIP-seq protocols, and Angel Montero Carcaboso generously provided the patient-derived cell line pGBM002 (HSJD-GBM-002). We are grateful to the University College London Cancer Institute Genomics core facility for performing the next-generation mRNA sequencing and to the Wellcome Trust for providing the mass spectrometry large equipment (Multiuser Equipment Grant 208402/Z/17/Z). Primary fetal NSCs were provided by the Glioma Cellular Genetics Resource (www.gcgr.org.uk). The project was supported by a grant from the Children with Cancer UK Charity (15/189). R.B.B. was supported by a PhD fellowship from the Science Without Borders Program (CAPES, Governo Dilma Rousseff, Brazil) and a postdoctoral fellowship from the European Molecular Biology Organization (EMBO). G.M.M. was supported by the Cancer Research UK Centre Accelerator Award (A21922). S.M.P is a Cancer Research UK Senior Research Fellow (A17368). R.B.B. and S.M.P. conceived the project and designed the experiments. R.B.B. performed the majority of the bench-based experimentation and data analyses. B.S. J.A. and S.T. performed the bioinformatic analyses. N.A. L.B. and M.A.M.-T. performed xenotransplantations and histological analyses. C.B. performed immunoprecipitations and western blotting procedures. J.C.W. and A.K. performed MS analysis. K.M.F and F.R. performed FOXG1 loss-of-function experiments. V.G. C.A.C.W. K.M.F. and G.M.M. provided technical assistance with derivation and characterization of cell lines, and R.A.A. provided human fetal tissues. R.B.B. and S.M.P. co-wrote the manuscript. S.M.P. is a founder and shareholder of Cellinta Ltd. a biotechnology startup that is developing cancer therapeutics, including glioblastoma. S.M.P. is also an inventor on a University of Edinburgh patent related to NSC culture methods (WO2005121318A3). The other authors declare no competing interests.

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