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; Marqués-Torrejón, María Ángeles; Morrison, Gillian; Ashmore, James; Robertson, Faye L.; Williams, Charles A. C.; Bradley, Leanne; Kriegsheim, Alex von; Anderson, Richard A.; Tomlinson, Simon R.; Pollard, Steven M.

doi:10.1016/j.stem.2021.01.016

Cited by 47 publications

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“…We therefore reasoned that human NSCs derived from the fetal hindbrain would represent a developmentally relevant model to investigate the role of H3.3-K27M. Supporting this, we recently demonstrated that human fetal hindbrain NSC cultures recapitulate defining transcriptional features of primary K27M-mutant tumors and, as opposed to forebrainderived NSCs, are sensitized to H3.3-K27M oncogenic activity 29 . Therefore, we used this model to dissect the transcriptional and epigenomic consequences of H3.3-K27M during early stages of gliomagenesis by stably expressing epitope-tagged H3.3 (wildtype or K27M) in hindbrain NSC cultures from two independent human fetal specimens (GCGR-NS19 and GCGR-NS13; see Methods) (Fig.…”

Section: An Isogenic Human Hindbrain Nsc Model Of K27m Mutant Diseasementioning

confidence: 95%

“…Human GCGR-NS19 and GCGR-NS13 cell lines were provided by the Glioma Genetics Resource (www.gcgr.org.uk). The cell lines were derived from the brainstem region of 19-and 13.5-week-old human fetuses, respectively, as previously described 29 Technologies), 20 ng/ml human EGF, 20 ng/ml human bFGF, 10 ng/ml human PDGF-AA, 10 ng/ml human PDGF-BB (all from Peprotech), 5 IU/ml heparin (Sigma) and Laminin-1 (R&D Systems, 2-4 μg/ml).…”

Section: Cell Culturementioning

confidence: 99%

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Simultaneous disruption of PRC2 and enhancer function underlies histone H3.3-K27M oncogenic activity in human hindbrain neural stem cells

et al. 2021

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Driver histone H3-K27M mutations are frequent in pediatric midline brain tumors. However, the precise mechanisms by which H3-K27M causes tumor initiation remain unclear. Here, we use human hindbrain neural stem cells to model the consequences of H3.3-K27M on the epigenomic landscape in a relevant developmental context.Genome-wide mapping of epitope-tagged histone H3.3 reveals that both wildtype and K27M-mutant incorporate abundantly at pre-existing active enhancers and promoters, and to a lesser extent at PRC2-bound regions. At active enhancers, H3.3-K27M leads to focal H3K27ac loss, decreased chromatin accessibility, and reduced transcriptional expression of nearby neurodevelopmental genes. In addition, H3.3-K27M deposition at a subset of PRC2 target genes leads to increased PRC2 and PRC1 binding and augmented transcriptional repression that can be partially reversed by PRC2 inhibitors. Our work suggests that rather than imposing de novo transcriptional circuits, H3.3-K27M drives tumorigenesis by locking initiating cells in their pre-existing, immature epigenomic state, via disruption of PRC2 and enhancer functions.

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Section: An Isogenic Human Hindbrain Nsc Model Of K27m Mutant Diseasementioning

confidence: 95%

Section: Cell Culturementioning

confidence: 99%

Simultaneous disruption of PRC2 and enhancer function underlies histone H3.3-K27M oncogenic activity in human hindbrain neural stem cells

et al. 2021

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“…Analysis of comprehensive single‐cell transcriptomic atlases of the developing brain and experimentally induced loss in specific cell types may also reveal the cell types, developmental periods and brain regions that are most susceptible to epigenetic perturbation causing brain tumours. The rare cancers driven by H3 mutations are likely intimately linked with restricted developmental contexts and cell‐type lineages that are permissive to their chromatin remodelling effects, as also suggested by a recent study [86]. These altered chromatin states may be promoting indefinite progenitor cell renewal, cell proliferation and acquisition of subsequent genetic alterations, ultimately leading to tumour formation.…”

Section: Discussionmentioning

confidence: 84%

Oncohistones: a roadmap to stalled development

et al. 2021

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Since the discovery of recurrent mutations in histone H3 variants in pediatric brain tumours, so-called 'oncohistones' have been identified in various cancers. While their mechanism of action remains under active investigation, several studies have shed light on how they promote genome-wide epigenetic perturbations. These findings converge on altered post-translational modifications on two key lysine (K) residues of the H3 tail, K27 and K36, which regulate several cellular processes, including those linked to cell differentiation during development. We will review how these oncohistones affect the methylation of cognate residues, but also disrupt the distribution of opposing chromatin marks, creating genome-wide epigenetic changes which participate in the oncogenic process. Ultimately, tumorigenesis is promoted through the maintenance of a progenitor state at the expense of differentiation in defined cellular and developmental contexts. As these epigenetic disruptions are reversible, improved understanding of oncohistone pathogenicity can result in needed alternative therapies. Accepted ArticleThis article is protected by copyright. All rights reserved A number of cancers carry recurrent, somatic, gain-of-function, heterozygous mutations in different histone 3 (H3)-encoding genes, which lead to amino acid substitutions on key residues of the H3 tail. These hotspot H3 mutations, oncohistones as we label them, were first identified in a deadly brain cancer, pediatric high-grade gliomas (pHGGs), where they account for a large proportion of these tumours. Notably, they show remarkable spatio-temporal specificity, indicating that their pathogenesis may be closely linked to aberrant development [1,2]. Indeed, HGGs of the central nervous system midline (which includes the pons, thalamus and spine) target younger children, and show a high frequency (~80%) of H3 lysine to methionine, or rarely to isoleucine, substitutions (K27M/I). These K27M/I mutations occur in either canonical H3.1/H3.2 variants mainly in the pons, or in the non-canonical H3.3 variant across all brain midline structures (Figure 1) [2][3][4][5][6]. By contrast, in HGGs of the brain hemispheres, glycine 34 to arginine or valine (G34R/V) substitutions are specific to H3F3A, which encodes the H3.3 variant, and target primarily the temporo-parietal cortex in adolescents and young adults, where they account for ~30% of these tumours [2][3][4][5][6]. Other hemispheric H3 wild-type gliomas of adolescents and young adults (mean age of 33 years) occur primarily in fronto-parietal lobes and carry non-overlapping truncating mutations in SETD2 [7], the only H3K36 tri-methyltransferase in humans, and/or hotspot somatic mutations in isocitrate dehydrogenases 1/2 (IDH1/2) [3,6,[8][9][10]. IDH mutations generate a neomorphic enzyme and excess production of the oncometabolite 2-hydroxyglutarate, which competitively inhibits histone and DNA demethylases to affect the methylation of K residues on the H3 tail and promote a CpG island methylator phenotype (CIMP). Together, ...

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“…While this work was processed for submission, highly related findings were reported, using expression of the fusion protein in murine HSPCs to show the importance of Tip60 interaction and downstream histone acetylation for leukemogenesis (Li et al, 2021). Furthermore, the onco-histone mutation H3.3G34R in pediatric high grade glioblastoma has been linked to impaired recruitment of ZMYND11 and its repressor function on highly expressed genes, promoting tumorigenesis by stabilizing expression of key progenitor genes (Bressan et al, 2021), which is a mechanism reminiscent of the one described for the fusion. As mistargeting of the NuA4/TIP60 complex seems to be the main mechanism employed by the ZMYND11-MBTD1 fusion, it can be most interesting to test some specific KAT5/Tip60 HAT inhibitors (Gao et al, 2014) (Coffey et al, 2012) to determine if de novo acetylation at coding regions is indeed the main oncogenic driving force in this specific group of acute myeloid leukemia, as suggested by the parallel study (Li et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it was shown that, in immune cells, stimulation-induced H3.3S31 phosphorylation leads to ejection of ZMYND11, allowing rapid transcriptional activation (Armache et al, 2020). Similarly, the H3.3G34R histone mutation linked to pediatric highgrade gliomas is also linked to displacement of ZMYND11 from chromatin (Bressan et al, 2021). MBTD1 (Malignant Brain Tumor Domain-containing protein 1) was originally identified in the Polycomb Group family of proteins because of its 4 MBT domains.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic ZMYND11-MBTD1 fusion protein anchors the NuA4/TIP60 histone acetyltransferase complex to the coding region of active gene

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et al. 2021

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A chromosomal translocation found in cannibalistic acute myeloid leukemia (AML) leads to an in-frame fusion of the transcription elongation repressor ZMYND11 to MBTD1, a subunit of the NuA4/TIP60 histone acetyltransferase (HAT) complex. In contrast to the NuA4/TIP60 complex, ZMYND11 is linked to repression of actively transcribed genes through recognition of H3.3K36me3. To understand the abnormal molecular events that expression of this ZMYND11-MBTD1 fusion protein can create, we performed its biochemical and functional characterization in comparison to each individual fusion partner. ZMYND11-MBTD1 is stably incorporated into the endogenous NuA4/TIP60 complex but does not bring any additional interactors as the fusion lacks the MYND domain of ZMYND11. Nevertheless, this truncated ZMYND11 moiety in the fusion mostly leads to mislocalization of the NuA4/TIP60 complex on the body of genes normally bound by ZMYND11 in the genome. This can be correlated to increased chromatin acetylation and altered gene transcription, most notably on the MYC oncogene. Importantly, expression of ZMYND11-MBTD1, but not the individual fusion partners, during embryonic stem cell differentiation, leads to decreased expression of specific differentiation markers, while favoring Myc-driven pluripotency. Altogether, these results indicate that the ZMYND11-MBTD1 fusion protein functions primarily by mistargeting the NuA4/TIP60 complex to the body of genes, altering normal transcription of specific genes, likely driving oncogenesis in part through the Myc regulatory network.

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

Cited by 47 publications

References 84 publications

Simultaneous disruption of PRC2 and enhancer function underlies histone H3.3-K27M oncogenic activity in human hindbrain neural stem cells

Simultaneous disruption of PRC2 and enhancer function underlies histone H3.3-K27M oncogenic activity in human hindbrain neural stem cells

Oncohistones: a roadmap to stalled development

Oncogenic ZMYND11-MBTD1 fusion protein anchors the NuA4/TIP60 histone acetyltransferase complex to the coding region of active gene

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