H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas

Pathania, Manav; Jay, Nicolas; Maestro, Nicola; Harutyunyan, Ashot S.; Nitarska, Justyna; Pahlavan, Pirasteh; Henderson, Stephen; Mikael, Leonie G.; Richard-Londt, Angela; Zhang, Ying; Costa, Joana R.; Hebert, Steven C.; Khazaei, Sima; Ibrahim, Nisreen; Herrero, Javier; Riccio, Antonella; Albrecht, Steffen; Ketteler, Robin; Brandner, Sebastian; Kleinman, Claudia L.; Jabado, Nada; Salomoni, Paolo

doi:10.1016/j.ccell.2017.09.014

Cited by 200 publications

(208 citation statements)

References 70 publications

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“…Our results are consistent with a broader mechanism of K-to-M substitutions as evidenced in S. pombe wherein H3K9M induces a gain in H3K9me3 and its methyltransferase (Clr4) at H3K9me3 nucleation sites, while H3K9me3 spreading across domains is lost (16). Our results account for the recent descriptions of H3K27M isogenic and glioma cells wherein there is a focal gain in H3K27me3 at previously established PRC2 target loci that are CpG island-dense (5,7,8,12). Thus, by impairing allosteric activation of PRC2 and thus spreading of H3K27me3 (25,27), H3K27M achieves both a global loss of H3K27me3 and yet, a focal accumulation of H3K27me3 at PRC2 recruitment sites.…”

Section: Inhibition Of Allosteric Activation Of Prc2 and Spreading Ofsupporting

confidence: 91%

“…Despite affecting only one of 15 copies of the H3 genes, the presence of H3K27M significantly impairs the activity of PRC2, leading to a drastic reduction and re-distribution of di-and tri-methylation of H3K27 [H3K27me2 and -3; (3-6)] in the affected cells. These effects of H3K27M on PRC2, as well as those on the chromatin landscape have been linked to oncogenic transcriptional programs that give rise to the cancer stem cell-like and proliferative properties of DIPG (4,7,8). Therefore, understanding the underlying mechanisms of how H3K27M affects PRC2 and the global epigenetic landscape is imperative for understanding DIPG and ultimately, devising strategic ways to overcome the oncogenic potential of H3K27M.…”

Section: Introductionmentioning

confidence: 99%

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Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

Stafford

Lee

Voigt³

et al. 2018

Preprint

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A methionine substitution at lysine 27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits PRC2 in a dominant negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found this interaction on chromatin is transient with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-chromatin suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to K27M leading to a failure to spread H3K27me3 at distinct foci. In turn, levels of Polycomb antagonists such as H3K36me2 are elevated suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity. MAIN TEXT

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Section: Inhibition Of Allosteric Activation Of Prc2 and Spreading Ofsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

Stafford

Lee

Voigt³

et al. 2018

Preprint

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“…These results are in concordance with a recent report in which authors developed an in utero electroporation-based method to model diffuse intrinsic pontine glioma (DIPG) with p53 knock down alone or p53 + Atrx knock downs in combination, to study the molecular mechanisms of H3.3K27M mutation on these genetic backgrounds. They found that only 29% (2/7) of the K27M-shp53 group displayed tumors at 4–6 months compared to 65% (11/17) for the K27M-shp53-shAtrx group, suggesting that Atrx knock down could be accelerating tumor development in this model as well [18]. Another report found that although ESCs harboring shRNAs against p53, Atrx and IDH grew slower in vitro when compared to ESCs harboring p53 shRNA and IDH mutation, these cells showed enhanced infiltration in an in vivo invasion assay, pointing to increased aggressiveness in association with ATRX knock down [19].…”

Section: Introductionmentioning

confidence: 99%

Mutant ATRX: uncovering a new therapeutic target for glioma

Haase

Garcia-Fabiani

Carney

et al. 2018

Expert Opinion on Therapeutic Targets

111

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Introduction ATRX is a chromatin remodeling protein whose main function is the deposition of the histone variant H3.3. ATRX mutations are widely distributed in glioma, and correlate with alternative lengthening of telomeres (ALT) development, but they also affect other cellular functions related to epigenetic regulation. Areas covered We discuss the main molecular characteristics of ATRX, from its various functions in normal development to the effects of its loss in ATRX syndrome patients and animal models. We focus on the salient consequences of ATRX mutations in cancer, from a clinical to a molecular point of view, focusing on both adult and pediatric glioma. Finally, we will discuss the therapeutic opportunities future research perspectives. Expert opinion ATRX is a major component of various essential cellular pathways, exceeding its functions as a histone chaperone (e.g., DNA replication and repair, chromatin higher-order structure regulation, gene transcriptional regulation, etc.). However, it is unclear how the loss of these functions in ATRX-null cancer cells affects cancer development and progression. We anticipate new treatments and clinical approaches will emerge for glioma and other cancer types as mechanistic and molecular studies on ATRX are only just beginning to reveal the many critical functions of this protein in cancer.

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“…The expression of EZHIP or H3 K27M impairs the dynamic regulation of H3K27me3 by impeding its production by PRC2. The proposed cell-of-origin for PFA ependymomas is radial glia that serve as CNS progenitor cells, and a recent single cell sequencing study points to oligodendroglial progenitors as the likely cellof-origin for DIPGs 8, 21,41,54,55 . Previous studies have found that H3 K27M impedes differentiation of neural precursor cells (NPCs) likely due to their inability to effectively silence genes involved in proliferation and multipotency 18,41 .…”

Section: Cellular Differentiation In Normal Development Includes Dynamentioning

confidence: 99%

PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism

Jain

Truman

Lund

et al. 2019

Preprint

Self Cite

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Polycomb group (PcG) proteins are essential for development and are frequently misregulated in human cancers. Polycomb Repressive Complexes (PRC1, PRC2) function in a collaborative epigenetic cross-talk with H3K27me3 to initiate and maintain transcriptional silencing. Diffuse intrinsic pontine gliomas (DIPGs) have extremely low H3K27me3 levels mediated by H3 K27M oncohistone. Posterior fossa type A (PFA) ependymomas also exhibit very low H3K27 methylation but lack the K27M oncohistone. Instead, PFA tumors express high levels of EZHIP (Enhancer of Zeste Homologs Inhibitory Protein, also termed CXORF67). We find that a highly conserved sequence within the C-terminus of EZHIP is necessary and sufficient to inhibit the catalytic activity of PRC2 in vitro and in vivo. Our biochemical experiments indicate that EZHIP directly interacts with the active site of the EZH2 subunit in a mechanism that is remarkably similar to the K27M oncohistone. Furthermore, expression of H3 K27M or EZHIP in cells promote similar chromatin profiles: loss of broad H3K27me3 domains, but retention of H3K27me3 at the sites of PRC2 recruitment. Importantly, we find that H3K27me3-mediated allosteric activation of PRC2 substantially increases the inhibition potential of EZHIP and H3 K27M, providing a potential mechanism for loss of H3K27me3 spreading from CpG islands in vivo. Our data indicate that PFA ependymoma and DIPG are driven in part by the action of peptidyl PRC2 inhibitors-the K27M oncohistone and the EZHIP 'oncohistone-mimic'-that dysregulate gene silencing to promote tumorigenesis. Covalent modifications to both DNA and histone proteins allow chromatin to act as a dynamic information hub that integrates diverse biochemical stimuli to regulate genomic DNA access to the transcription machinery and ultimately establish and maintain cellular phenotypes. There is increasing appreciation that aberrant chromatin modifications are involved in the pathogenesis of cancer. Nowhere is this better supported than with the groundbreaking discoveries of highfrequency, somatic mutations in histones that are drivers of oncogenesis.

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H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas

Cited by 200 publications

References 70 publications

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

Mutant ATRX: uncovering a new therapeutic target for glioma

PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism

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