Inhibition of PRC2 Activity by a Gain-of-Function H3 Mutation Found in Pediatric Glioblastoma
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EZ Inhibition: Missense mutations in the core constituents of the genome packaging material, chromatin, have been implicated in several of human cancers. Nucleosomes are made up of histones, and a mutation of lysine 27 (K27) to methionine in the N-terminal tail of histone variants H3.3 and H3.1 has been identified in various pediatric gliomas. Lewis et al. (p. 857 , published online 28 March; see the Perspective by Morgan and Shilatifard ) show that the polycomb enzyme complex, which can epigenetically modify K27 by addition of a methyl group—and which is often a silencing signal—is itself potently inhibited by replacement of the H3.3/3.1 K27 by methionine. The inhibition of the EZH2 subunit causes an overall reduction of K27 methylation. Methionine mutants of other methylated lysine residues in histone H3 cause similar reductions in methylation levels of the cognate lysine, altering the epigenetic profiles of such cancer cells.
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Tumor cells with the K27M mutation exhibit low levels of H3K27me3 and aberrant gene silencing.
“Consequently, tumor cells with the K27M mutation exhibit low levels of H3K27me3 and aberrant gene silencing (4,(7)(8)(9).”
From <i>S</i> -adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3 (2016) · cites this paper as [7]
The paper reports that K27M-mutant DIPG tumors have significantly less H3K27me3 than non-mutant tumors (indexed Abstract, Fig. 1 discussion). Its concluding passage proposes aberrant epigenetic silencing as a model, but does not establish that these tumor cells exhibit aberrant gene silencing as a measured finding. (LLM, conf=0.88)
Experimental — accuracy not yet measuredH3.3K27M acts in a dominant manner to deplete H3K27 methylation by inhibiting PRC2 methyltransferase activity.
“act in a dominant manner to deplete H3K27 methylation by inhibiting PRC2 methyltransferase activity [5, 6]”
From Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling (2014) · cites this paper as [6]
Additional histone H3 lysine-to-methionine mutants possess dominant gain-of-function activities.
“Additional histone H3 lysine-to-methionine mutants possess dominant gain-of-function activities [6]”
From Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling (2014) · cites this paper as [6]
K-to-M oncohistones transform histone H3 proteins into potent inhibitors of specific lysine methyltransferase enzymes.
“We and others previously showed that K-to-M oncohistones transform the histone H3 proteins into potent inhibitors of specific lysine methyltransferase enzymes (4-7).”
From <i>S</i> -adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3 (2016) · cites this paper as [7]
The K27M mutation found in pediatric glioma is sufficient to transform histone H3 into a potent inhibitor of enzymatic activity of PRC2.
“Previous studies showed that the K27M mutation found in pediatric glioma is sufficient to transform histone H3 into a potent inhibitor of enzymatic activity of PRC2 (4, 5, 7).”
From <i>S</i> -adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3 (2016) · cites this paper as [7]
H3K9M peptides are capable of inhibiting activity of SUV39H1 and G9a, two H3K9-directed methyltransferases, in vitro.
“we previously showed that H3K9M peptides are capable of inhibiting activity of SUV39H1 and G9a, two H3K9-directed methyltransferases, in vitro (7).”
From <i>S</i> -adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3 (2016) · cites this paper as [7]
Only long, unbranched hydrophobic side chains containing methionine (M) and isoleucine (I) at lysine 27 (K27M and K27I) are capable of inhibiting PRC2 in vitro and decreasing H3K27me3 when expressed ectopically in cultured cells.
“Previously, we found that only long, unbranched hydrophobic side chains containing methionine (M) and isoleucine (I) at lysine 27 (K27M and K27I) were capable of inhibiting PRC2 in vitro and decreasing H3K27me3 when expressed ectopically in cultured cells (7).”
From <i>S</i> -adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3 (2016) · cites this paper as [7]
Despite reports supporting a higher affinity of PRC2 for H3K27M as compared with wild-type H3, H3K27M was often inversely correlated with PRC2 occupancy, challenging the idea that H3K27M sequesters PRC2 on chromatin.
“Despite reports supporting a higher affinity of PRC2 for H3K27M as compared with wild-type H3 108-110 , H3K27M was often inversely correlated with PRC2 occupancy, challenging the idea that H3K27M sequesters PRC2 on chromatin 111,112 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [112]
Expression of the H3K27M mutant histone is accompanied by reduced PRC2-mediated H3K27 trimethylation.
“Expression of the histone mutant is accompanied by a reduction in the levels of Polycomb Repressive Complex 2 (PRC2) mediated H3K27 trimethylation (H3K27me3) and this is purported to be a driving event of DIPG oncogenesis4,5.”
From Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas (2017) · cites this paper as [4]
When H3K27me3 is lost, these nucleosomes acquire H3K27ac and form H3K27M-K27ac heterotypic nucleosomes.
“Interestingly upon loss of H3K27me3 these nucleosomes acquire H3K27ac resulting in the formation of H3K27M-K27ac heterotypic nucleosomes4 (Figure 1D and Supplementary Fig. 5B–C).”
From Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas (2017) · cites this paper as [4]
H3K27M expression is associated with increased H3K27ac levels.
“As shown by our group and others, H3K27M expression is associated with increased levels of H3K27ac4,5 (Fig. 1D).”
From Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas (2017) · cites this paper as [4]
PRC2 catalytic activity toward H3K27M-containing nucleosomes is strongly inhibited.
“Although still functionally active, PRC2 catalytic property toward H3K27M containing nucleosomes is strongly inhibited4.”
From Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas (2017) · cites this paper as [4]
H3K27M in DIPG cells does not appear to recruit or sequester EZH2 or PRC2.
“Collectively, these results strongly indicate that H3K27M in DIPG cells does not appear to recruit or sequester EZH2 (or in general PRC2), as suggested by other studies4,6,7.”
From Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas (2017) · cites this paper as [4]
Attempts to model H3.3K27M-driven high-grade glioma by genetic recombination in postnatal neural progenitor/stem cells failed to demonstrate tumor-driving activity.
“Attempts to model H3.3K27M-driven HGG formation in vivo via genetic recombination in neural progenitor/stem cells (NPCs) in the postnatal brain failed to demonstrate tumor-driving activity”
From H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas (2017) · cites this paper as Lewis et al., 2013
H3.3K27M has gain-of-function activity that inhibits PRC2, leading to a global reduction in H3K27me3 levels in primary tumors and tumor-derived primary cells.
“H3.3K27M has been shown to have gain-of-function activity inhibiting the Polycomb Repressive Complex 2 (PRC2) (Bender et al., 2013; Lewis et al., 2013), which in turn leads to a global reduction in H3K27me3 levels in primary tumors and tumor-derived primary cells.”
From H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas (2017) · cites this paper as Lewis et al., 2013
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Cites
The Polycomb complex PRC2 and its mark in life
Margueron, R., & Reinberg, D. (2011) · Nature · doi:10.1038/nature09784 · Cited by 3,347 · see citing works
Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma
Schwartzentruber, J., Korshunov, A., Liu, X.-Y., Jones, D. T. W., Pfaff, E., Jacob, K., Sturm, D., Fontebasso, A. M., Quang, D.-A. K., Tönjes, M., et al. (2012) · Nature · doi:10.1038/nature10833 · Cited by 2,631 · see citing works
St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project (2012) · Nature Genetics · doi:10.1038/ng.1102 · Cited by 1,724 · see citing works
Taverna, S. D., Li, H., Ruthenburg, A. J., Allis, C. D., & Patel, D. J. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1338 · Cited by 1,419 · see citing works
Self-citationRole of the polycomb protein EED in the propagation of repressive histone marks
Margueron, R., Justin, N., Ohno, K., Sharpe, M. L., Son, J., Drury, W. J., Voigt, P., Martin, S. R., Taylor, W. R., Marco, V. D., et al. (2009) · Nature · doi:10.1038/nature08398 · Cited by 1,203 · see citing works
Khuong-Quang, D.-A., Buczkowicz, P., Rakopoulos, P., Liu, X.-Y., Fontebasso, A. M., Bouffet, E., Bartels, U., Albrecht, S., Schwartzentruber, J., Letourneau, L., et al. (2012) · Acta Neuropathologica · doi:10.1007/s00401-012-0998-0 · Cited by 1,028 · see citing works
Roles of the EZH2 histone methyltransferase in cancer epigenetics
Simon, J. A., & Lange, C. A. (2008) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2008.07.010 · Cited by 860 · see citing works
Sneeringer, C. J., Scott, M. P., Kuntz, K. W., Knutson, S. K., Pollock, R. M., Richon, V. M., & Copeland, R. A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1012525107 · Cited by 691 · see citing works
Yap, D., Chu, J., Berg, T., Schapira, M., Cheng, S., Moradian, A., Morin, R. D., Mungall, A. J. J., Meissner, B., Boyle, M., et al. (2010) · Blood · doi:10.1182/blood-2010-11-321208 · Cited by 609 · see citing works
A Novel Mammalian Flavin-dependent Histone Demethylase
Karytinos, A., Forneris, F., Profumo, A., Ciossani, G., Battaglioli, E., Binda, C., & Mattevi, A. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.003087 · Cited by 274 · see citing works
Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferasePreprint
Couture, J., Collazo, E., Brunzelle, J. S., & Trievel, R. C. (2005) · Genes & Development · doi:10.1101/gad.1318405 · Cited by 222 · see citing works
Xu, C., Bian, C., Yang, W., Galka, M., Ouyang, H., Chen, C., Qiu, W., Liu, H., Jones, A. E., MacKenzie, F., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008937107 · Cited by 221 · see citing works
Becher, O. J., Hambardzumyan, D., Walker, T. R., Helmy, K. Y., Nazarian, J., Albrecht, S., Hiner, R. L., Gall, S., Huse, J. T., Jabado, N., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-2503 · Cited by 163 · see citing works
Self-citationNew Epigenetic Drivers of Cancers
Elsässer, S. J., Allis, C. D., & Lewis, P. W. (2011) · Science · doi:10.1126/science.1203280 · Cited by 82 · see citing works
Self-citation
Flagged first, then by citations
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Cited by
Sorted by citations
The molecular hallmarks of epigenetic control
Allis, C. D., & Jenuwein, T. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.59 · Cited by 2,809 · see citing works
Self-citationKim, K. H., & Roberts, C. W. M. (2016) · Nature Medicine · doi:10.1038/nm.4036 · Cited by 1,471 · see citing works
Epigenetic plasticity and the hallmarks of cancer
Flavahan, W. A., Gaskell, E., & Bernstein, B. E. (2017) · Science · doi:10.1126/science.aal2380 · Cited by 1,340 · see citing works
Epigenetic Determinants of CancerPreprint
Baylin, S. B., & Jones, P. A. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a019505 · Cited by 1,363 · see citing works
Genome Regulation by Polycomb and Trithorax: 70 Years and Counting
Schuettengruber, B., Bourbon, H.-M., Di Croce, L., & Cavalli, G. (2017) · Cell · doi:10.1016/j.cell.2017.08.002 · Cited by 1,094 · see citing works
Metabolic regulation of gene expression through histone acylations
Sabari, B. R., Zhang, D., Allis, C. D., & Zhao, Y. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.140 · Cited by 1,134 · see citing works
Self-citationWu, G., Li, Y., Qu, C., Chen, X. '., Edmonson, M. N., Ma, X., Nagahawatte, P., Hedlund, E., Rusch, M., Huether, R., et al. (2014) · Nature Genetics · doi:10.1038/ng.2938 · Cited by 1,101 · see citing works
Cancer Epigenetics: Tumor Heterogeneity, Plasticity of Stem-like States, and Drug Resistance
Easwaran, H., Tsai, H.-C., & Baylin, S. B. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.05.015 · Cited by 915 · see citing works
Epigenetic modulators, modifiers and mediators in cancer aetiology and progression
Feinberg, A. P., Koldobskiy, M. A., & Göndör, A. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.13 · Cited by 878 · see citing works
Bender, S., Tang, Y., Lindroth, A. M., Hovestadt, V., Jones, D. T. W., Kool, M., Zapatka, M., Northcott, P. A., Sturm, D., Wang, W., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.10.006 · Cited by 818 · see citing works
Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone
Behjati, S., Tarpey, P. S., Presneau, N., Scheipl, S., Pillay, N., Van Loo, P., Wedge, D. C., Cooke, S. L., Gundem, G., Davies, H., et al. (2013) · Nature Genetics · doi:10.1038/ng.2814 · Cited by 854 · see citing works
Metabolic reprogramming and epigenetic modifications on the path to cancer
Sun, L., Zhang, H., & Gao, P. (2021) · Protein & Cell · doi:10.1007/s13238-021-00846-7 · Cited by 796 · see citing works
Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq
Filbin, M. G., Tirosh, I., Hovestadt, V., Shaw, M. L., Escalante, L. E., Mathewson, N. D., Neftel, C., Frank, N., Pelton, K., Hebert, C. M., et al. (2018) · Science · doi:10.1126/science.aao4750 · Cited by 699 · see citing works
Advances in the molecular genetics of gliomas — implications for classification and therapy
Reifenberger, G., Wirsching, H.-G., Knobbe-Thomsen, C. B., & Weller, M. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.204 · Cited by 662 · see citing works
Functionally defined therapeutic targets in diffuse intrinsic pontine glioma
Grasso, C. S., Tang, Y., Truffaux, N., Berlow, N. E., Liu, L., Debily, M.-A., Quist, M. J., Davis, L. E., Huang, E. C., Woo, P. J., et al. (2015) · Nature Medicine · doi:10.1038/nm.3855 · Cited by 687 · see citing works
Castel, D., Philippe, C., Calmon, R., Dret, L. L., Truffaux, N., Boddaert, N., Pagès, M., Taylor, K. R., Saulnier, P., Lacroix, L., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1478-0 · Cited by 663 · see citing works
Burr, M. L., Sparbier, C. E., Chan, K. L., Chan, Y.-C., Kersbergen, A. J., Lam, E. Y. N., Azidis-Yates, E., Vassiliadis, D., Bell, C. C., Gilan, O., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.08.008 · Cited by 656 · see citing works
The roles of DNA, RNA and histone methylation in ageing and cancer
Michalak, E. M., Burr, M. L., Bannister, A. J., & Dawson, M. A. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0143-1 · Cited by 549 · see citing works
Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge
Sturm, D., Bender, S., Jones, D. T. W., Lichter, P., Grill, J., Becher, O., Hawkins, C., Majewski, J., Jones, C., Costello, J. F., et al. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3655 · Cited by 555 · see citing works
Self-citationMethionine metabolism in health and cancer: a nexus of diet and precision medicine
Sanderson, S. M., Gao, X., Dai, Z., & Locasale, J. W. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0187-8 · Cited by 572 · see citing works
Stem cell programs in cancer initiation, progression, and therapy resistance
Huang, T., Song, X., Xu, D., Tiek, D., Goenka, A., Wu, B., Sastry, N., Hu, B., & Cheng, S.-Y. (2020) · Theranostics · doi:10.7150/thno.41648 · Cited by 524 · see citing works
EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas
Mohammad, F., Weissmann, S., Leblanc, B., Pandey, D. P., Højfeldt, J. W., Comet, I., Zheng, C., Johansen, J. V., Rapin, N., Porse, B. T., et al. (2017) · Nature Medicine · doi:10.1038/nm.4293 · Cited by 535 · see citing works
Glioma epigenetics: From subclassification to novel treatment options
Gusyatiner, O., & Hegi, M. E. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.11.010 · Cited by 547 · see citing works
The impact of cellular metabolism on chromatin dynamics and epigenetics
Reid, M. A., Dai, Z., & Locasale, J. W. (2017) · Nature Cell Biology · doi:10.1038/ncb3629 · Cited by 515 · see citing works
Epigenetic balance of gene expression by Polycomb and COMPASS families
Piunti, A., & Shilatifard, A. (2016) · Science · doi:10.1126/science.aad9780 · Cited by 524 · see citing works
Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma
Taylor, K. R., Mackay, A. G., Truffaux, N., Butterfield, Y. S. N., Morozova, O., Philippe, C., Castel, D., Grasso, C. S., Vinci, M., Carvalho, D. M., et al. (2014) · Nature Genetics · doi:10.1038/ng.2925 · Cited by 522 · see citing works
Regulation of chromatin and gene expression by metabolic enzymes and metabolites
Li, X., Egervári, G., Wang, Y., Berger, S. L., & Lu, Z. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0029-7 · Cited by 486 · see citing works
Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma
Fontebasso, A. M., Papillon-Cavanagh, S., Schwartzentruber, J., Nikbakht, H., Gerges, N., Fiset, P.-O., Bechet, D., Faury, D., De Jay, N., Ramkissoon, L. A., et al. (2014) · Nature Genetics · doi:10.1038/ng.2950 · Cited by 465 · see citing works
Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma
Hashizume, R., Andor, N., Ihara, Y., Lerner, R., Gan, H., Chen, X., Fang, D., Huang, X., Tom, M. W., Ngo, V., et al. (2014) · Nature Medicine · doi:10.1038/nm.3716 · Cited by 476 · see citing works
Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas
Piunti, A., Hashizume, R., Morgan, M. A., Bartom, E. T., Horbinski, C. M., Marshall, S. A., Rendleman, E. J., Ma, Q., Takahashi, Y.-H., Woodfin, A. R., et al. (2017) · Nature Medicine · doi:10.1038/nm.4296 · Cited by 445 · see citing works
Diffuse Glioma Heterogeneity and Its Therapeutic Implications
Nicholson, J., & Fine, H. A. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1474 · Cited by 459 · see citing works
Pfister, S. X., Ahrabi, S., Zalmas, L., Sarkar, S., Aymard, F., Bachrati, C. Z., Helleday, T., Legube, G., Thangue, N. B. L., Porter, A. C. G., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.05.026 · Cited by 465 · see citing works
Plass, C., Pfister, S. M., Lindroth, A. M., Bogatyrova, O., Claus, R., & Lichter, P. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3554 · Cited by 448 · see citing works
Solomon, D. A., Wood, M. D., Tihan, T., Bollen, A. W., Gupta, N. M., Phillips, J. J., & Perry, A. (2015) · Brain Pathology · doi:10.1111/bpa.12336 · Cited by 438 · see citing works
Chromatin proteins and modifications as drug targets
Helin, K., & Dhanak, D. (2013) · Nature · doi:10.1038/nature12751 · Cited by 435 · see citing works
Maintaining cell identity: PRC2-mediated regulation of transcription and cancer
Comet, I. V., Riising, E. M., Leblanc, B., & Helin, K. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.83 · Cited by 428 · see citing works
Resetting Epigenetic Memory by Reprogramming of Histone Modifications in Mammals
Zheng, H., Huang, B., Zhang, B., Xiang, Y., Du, Z., Xu, Q., Li, Y., Wang, Q., Ma, J., Xu, P., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.08.032 · Cited by 432 · see citing works
The roles of histone variants in fine-tuning chromatin organization and function
Martire, S., & Banaszynski, L. A. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0262-8 · Cited by 392 · see citing works
Self-citationHistone Variants and EpigeneticsPreprint
Henikoff, S., & Smith, M. M. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a019364 · Cited by 414 · see citing works
The language of chromatin modification in human cancers
Zhao, S., Allis, C. D., & Wang, G. G. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00357-x · Cited by 406 · see citing works
Self-citationStructural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2
Justin, N., Zhang, Y., Tarricone, C., Martin, S. R., Chen, S., Underwood, E., Marco, V. D., Haire, L. F., Walker, P. A., Reinberg, D., et al. (2016) · Nature Communications · doi:10.1038/ncomms11316 · Cited by 403 · see citing works
Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2
Jiao, L., & Liu, X. (2015) · Science · doi:10.1126/science.aac4383 · Cited by 402 · see citing works
Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation
Funato, K., Major, T., Lewis, P. W., Allis, C. D., & Tabar, V. (2014) · Science · doi:10.1126/science.1253799 · Cited by 390 · see citing works
Self-citationTranscriptional Dependencies in Diffuse Intrinsic Pontine Glioma
Nagaraja, S., Vitanza, N. A., Woo, P. J., Taylor, K. R., Liu, F., Zhang, L., Li, M., Meng, W., Ponnuswami, A., Sun, W., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.03.011 · Cited by 386 · see citing works
Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape
Lü, C., Jain, S. U., Hoelper, D., Béchet, D., Molden, R. C., Ran, L., Murphy, D. A., Venneti, S., Hameed, M., Pawel, B., et al. (2016) · Science · doi:10.1126/science.aac7272 · Cited by 392 · see citing works
Self-citationThe expanding landscape of ‘oncohistone’ mutations in human cancers
Nacev, B. A., Feng, L., Bagert, J. D., Lemiesz, A. E., Gao, J., Soshnev, A. A., Kundra, R., Schultz, N., Muir, T. W., & Allis, C. D. (2019) · Nature · doi:10.1038/s41586-019-1038-1 · Cited by 384 · see citing works
Self-citationThe landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes
Huether, R., Dong, L., Chen, X. '., Wu, G., Parker, M. D., Wei, L., Ma, J., Edmonson, M. N., Hedlund, E., Rusch, M., et al. (2014) · Nature Communications · doi:10.1038/ncomms4630 · Cited by 378 · see citing works
Kundu, S., Ji, F., Sunwoo, H., Jain, G., Lee, J. T., Sadreyev, R. I., Dekker, J., & Kingston, R. E. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.01.009 · Cited by 333 · see citing works
Pediatric high-grade glioma: biologically and clinically in need of new thinking
Jones, C., Karajannis, M. A., Jones, D., Kieran, M. W., Monje, M., Baker, S. J., Becher, O. J., Cho, Y., Gupta, N. M., Hawkins, C. E., et al. (2016) · Neuro-Oncology · doi:10.1093/neuonc/now101 · Cited by 360 · see citing works
Self-citationHarutyunyan, A. S., Krug, B., Chen, H., Papillon‐Cavanagh, S., Zeinieh, M. P., Jay, N. D., Deshmukh, S., Chen, C. C. L., Belle, J. I., Mikael, L. G., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09140-x · Cited by 348 · see citing works
Self-citationMorgan, M. A., & Shilatifard, A. (2020) · Nature Genetics · doi:10.1038/s41588-020-00736-4 · Cited by 352 · see citing works
Buczkowicz, P., Bartels, U. K., Bouffet, É., Becher, O. J., & Hawkins, C. E. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1319-6 · Cited by 350 · see citing works
Self-citationKorshunov, A., Ryzhova, M. V., Hovestadt, V., Bender, S., Sturm, D., Capper, D., Meyer, J., Schrimpf, D., Kool, M., Northcott, P. A., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1405-4 · Cited by 346 · see citing works
Maze, I. S., Noh, K., Soshnev, A. A., & Allis, C. D. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3673 · Cited by 347 · see citing works
Self-citationZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression
Wen, H., Li, Y., Xi, Y., Jiang, S., Stratton, S. A., Peng, D., Tanaka, K. Y., Ren, Y.-F., Xia, Z., Wu, J., et al. (2014) · Nature · doi:10.1038/nature13045 · Cited by 344 · see citing works
Epigenetics and Cancer Stem Cells: Unleashing, Hijacking, and Restricting Cellular Plasticity
Wainwright, E. N., & Scaffidi, P. (2017) · Trends in Cancer · doi:10.1016/j.trecan.2017.04.004 · Cited by 293 · see citing works
Pediatric Gliomas: Current Concepts on Diagnosis, Biology, and Clinical Management
Sturm, D., Pfister, S. M., & Jones, D. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2017.73.0242 · Cited by 333 · see citing works
Regulation of gene transcription by Polycomb proteins
Aranda, S., Martín, G. M., & Croce, L. D. (2015) · Science Advances · doi:10.1126/sciadv.1500737 · Cited by 332 · see citing works
Variants of core histones and their roles in cell fate decisions, development and cancer
Buschbeck, M., & Hake, S. B. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.166 · Cited by 343 · see citing works
H3K27 methylation: a promiscuous repressive chromatin mark
Wiles, E. T., & Selker, E. U. (2016) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2016.11.001 · Cited by 332 · see citing works
The Glioma Stem Cell Model in the Era of Single-Cell Genomics
Suvà, M. L., & Tirosh, I. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.04.001 · Cited by 325 · see citing works
Histone Chaperones: Assisting Histone Traffic and Nucleosome Dynamics
Gurard‐Levin, Z. A., Quivy, J., & Almouzni, G. (2014) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060713-035536 · Cited by 310 · see citing works
PRC2 binds active promoters and contacts nascent RNAs in embryonic stem cells
Kaneko, S., Son, J., Shen, S. S., Reinberg, D., & Bonasio, R. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2700 · Cited by 308 · see citing works
Glioblastoma at the crossroads: current understanding and future therapeutic horizons
Singh, S., Dey, D., Barik, D., Mohapatra, I., Kim, S., Sharma, M., Prasad, S., Wang, P., Singh, A. R., & Singh, G. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02299-4 · Cited by 332 · see citing works
Larson, J. D., Kasper, L. H., Paugh, B. S., Jin, H., Wu, G., Kwon, C.-H., Fan, Y., Shaw, T. I., Silveira, A. B., Qu, C., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.11.015 · Cited by 297 · see citing works
Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation
Pfister, S. X., Markkanen, E., Jiang, Y., Sarkar, S., Woodcock, M., Orlando, G., Mavrommati, I., Pai, C., Zalmas, L., Drobnitzky, N., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.09.015 · Cited by 300 · see citing works
Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma
Jones, C., & Baker, S. J. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3811 · Cited by 294 · see citing works
Karremann, M., Gielen, G. H., Hoffmann, M., Wiese, M., Colditz, N., Warmuth‐Metz, M., Bison, B., Claviez, A., van Vuurden, D. G., von Bueren, A. O., et al. (2017) · Neuro-Oncology · doi:10.1093/neuonc/nox149 · Cited by 293 · see citing works
Regulation and Role of EZH2 in Cancer
Yamaguchi, H., & Hung, M. (2014) · Cancer Research and Treatment · doi:10.4143/crt.2014.46.3.209 · Cited by 291 · see citing works
From profiles to function in epigenomics
Stricker, S. H., Köferle, A., & Beck, S. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.138 · Cited by 290 · see citing works
Marked for death: Targeting epigenetic changes in cancer
Pfister, S. X., & Ashworth, A. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.256 · Cited by 288 · see citing works
The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas
Fang, D., Gan, H., Lee, J., Han, J., Wang, Z., Riester, S. M., Jin, L. G., Chen, J., Zhou, H., Wang, J., et al. (2016) · Science · doi:10.1126/science.aae0065 · Cited by 285 · see citing works
Characteristics of H3 K27M-mutant gliomas in adults
Meyronet, D., Esteban-Mader, M., Bonnet, C., Joly, M., Uro‐Coste, E., Benouaich‐Amiel, A., Forest, F., Rousselot‐Denis, C., Burel‐Vandenbos, F., Bourg, V., et al. (2016) · Neuro-Oncology · doi:10.1093/neuonc/now274 · Cited by 282 · see citing works
A new world of Polycombs: unexpected partnerships and emerging functions
Schwartz, Y. B., & Pirrotta, V. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3603 · Cited by 277 · see citing works
Emerging role of tumor cell plasticity in modifying therapeutic response
Qin, S., Jiang, J., Lü, Y., Nice, E. C., Huang, C., Zhang, J., & He, W. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00313-5 · Cited by 274 · see citing works
Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma
Nikbakht, H., Panditharatna, E., Mikael, L. G., Li, R., Gayden, T., Osmond, M., Ho, C.-Y., Kambhampati, M., Hwang, E. I., Faury, D., et al. (2016) · Nature Communications · doi:10.1038/ncomms11185 · Cited by 252 · see citing works
Souweidane, M. M., Kramer, K., Pandit-Taskar, N. D., Zhou, Z., Haque, S. S., ZANZONICO, P. B., Carrasquillo, J. A., Lyashchenko, S. K., Thakur, S. B., Donzelli, M. A., et al. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30322-x · Cited by 267 · see citing works
Pathania, M., De Jay, N., Maestro, N., Harutyunyan, A. S., Nitarska, J., Pahlavan, P., Henderson, S., Mikael, L. G., Richard-Londt, A., Zhang, Y., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.09.014 · Cited by 264 · see citing works
PRC2 is high maintenancePreprint
Yu, J.-R., Lee, C., Oksuz, O., Stafford, J. M., & Reinberg, D. (2019) · Genes & Development · doi:10.1101/gad.325050.119 · Cited by 248 · see citing works
Korshunov, A., Capper, D., Reuss, D., Schrimpf, D., Ryzhova, M., Hovestadt, V., Sturm, D., Meyer, J., Jones, C., Zheludkova, O., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-015-1493-1 · Cited by 236 · see citing works
Panwalkar, P., Clark, J. R., Ramaswamy, V., Hawes, D., Yang, F., Dunham, C. P., Yip, S. S. F., Hukin, J., Sun, Y., Schipper, M. J., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1752-4 · Cited by 250 · see citing works
Histones: At the Crossroads of Peptide and Protein Chemistry
Müller, M. M., & Muir, T. W. (2015) · Chemical Reviews · doi:10.1021/cr5003529 · Cited by 247 · see citing works
Self-citationMolecular architecture of human polycomb repressive complex 2
Ciferri, C., Lander, G. C., Maiolica, A., Herzog, F., Aebersold, R. H., & Nogales, E. (2012) · eLife · doi:10.7554/elife.00005 · Cited by 246 · see citing works
PRC2 mediated H3K27 methylations in cellular identity and cancer
Conway, E., Healy, E., & Bracken, A. P. (2015) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2015.10.003 · Cited by 239 · see citing works
Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease
Bhat, K. P., Kanıskan, H. Ü., Jin, J. J., & Gozani, O. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-00108-x · Cited by 243 · see citing works
Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas
Papillon‐Cavanagh, S., Lü, C., Gayden, T., Mikael, L. G., Béchet, D., Karamboulas, C., Ailles, L., Karamchandani, J., Marchione, D. M., Garcia, B. A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3757 · Cited by 239 · see citing works
Self-citationKrug, B., Jay, N. D., Harutyunyan, A. S., Deshmukh, S., Marchione, D. M., Guilhamon, P., Bertrand, K. C., Mikael, L. G., McConechy, M. K., Chen, C. C. L., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.04.004 · Cited by 233 · see citing works
Self-citationZhao, S., Bellone, S., Lopez, S., Thakral, D., Schwab, C. L., English, D. P.-G., Black, J., Cocco, E., Choi, J., Zammataro, L. A., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1614120113 · Cited by 230 · see citing works
Guo, R., Zheng, L., Park, J. W., Lyu, R., Chen, H., Jiao, F., Xu, W., Mu, S.-R., Wen, H., Qiu, J., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.08.022 · Cited by 229 · see citing works
Causes of genome instability: the effect of low dose chemical exposures in modern society
Langie, S. A. S., Koppen, G., Desaulniers, D. M., Al‐Mulla, F., Al-Temaimi, R. A., Amedei, A., Azqueta, A., Bisson, W. H., Brown, D. G., Brunborg, G., et al. (2015) · Carcinogenesis · doi:10.1093/carcin/bgv031 · Cited by 229 · see citing works
Developmental origins and emerging therapeutic opportunities for childhood cancer
Filbin, M. G., & Monje, M. (2019) · Nature Medicine · doi:10.1038/s41591-019-0383-9 · Cited by 240 · see citing works
Targeting EZH2 in cancer therapy
Yamagishi, M., & Uchimaru, K. (2017) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000390 · Cited by 224 · see citing works
The interplay between DNA and histone methylation: molecular mechanisms and disease implications
Li, Y., Chen, X., & Lu, C. (2021) · The EMBO Reports · doi:10.15252/embr.202051803 · Cited by 223 · see citing works
Chromatin signatures of cancerPreprint
Morgan, M. A., & Shilatifard, A. (2015) · Genes & Development · doi:10.1101/gad.255182.114 · Cited by 214 · see citing works
The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex
He, Y., Selvaraju, S., Curtin, M. L., Jakob, C. G., Zhu, H., Comess, K. M., Shaw, B., The, J., Lima-Fernandes, E., Szewczyk, M. M., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2306 · Cited by 224 · see citing works
Black, J. C., Manning, A. L., Rechem, C. V., Kim, J., Ladd, B., Cho, J., Pineda, C. M., Murphy, N., Daniels, D. L., Montagna, C., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.051 · Cited by 214 · see citing works
Self-citationRole of the Polycomb Repressive Complex 2 (PRC2) in Transcriptional Regulation and CancerPreprint
Laugesen, A., Højfeldt, J. W., & Helin, K. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026575 · Cited by 214 · see citing works
Nacev, B. A., Jones, K. B., Intlekofer, A. M., Yu, J., Allis, C. D., Tap, W. D., Ladanyi, M., & Nielsen, T. O. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0288-4 · Cited by 211 · see citing works
Self-citationLiu, I., Jiang, L., Samuelsson, E. R., Salas, S. M., Beck, A., Hack, O. A., Jeong, D., Shaw, M. L., Englinger, B., LaBelle, J. J., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01236-3 · Cited by 213 · see citing works
Molecular analysis of PRC2 recruitment to DNA in chromatin and its inhibition by RNA
Wang, X., Paucek, R. D., Gooding, A. R., Brown, Z. Z., Ge, E. J., Muir, T. W., & Cech, T. R. (2017) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3487 · Cited by 211 · see citing works
Self-citation
- Authors
- Lewis, P. W., Müller, M. M., Koletsky, M. S., Cordero, F., Lin, S., Banaszynski, L. A., Garcia, B. A., Muir, T. W., Becher, O. J., & Allis, C. D.
- Affiliations
- Rockefeller University (US)
- Princeton University (US)
- Duke University (US)
- University of Pennsylvania (US)
- Corresponding author
- Allis, C. David
- ORCID
- Venue
- Science
- Published
- 2013-05-17
- Volume
- 340
- Issue
- 6134
- Pages
- 857-861
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3951439
- OpenAlex
- W1995105508
- Cited by
- 1,345
- References
- 14
- Citations by year
- 2026: 73 · 2025: 82 · 2024: 103 · 2023: 106 · 2022: 103 · 2021: 118 · 2020: 146 · 2019: 112 · 2018: 84 · 2017: 102 · 2016: 90 · 2015: 95 · 2014: 87 · 2013: 40 · 2012: 1
- FWCI
- 51.21
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- National Institutes of Health (DP2OD007447)
- National Institute of Mental Health (P50MH096890)
- National Institute of General Medical Sciences (GM040922, R01GM107047, R01GM040922)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- pediatric glioblastoma, diffuse intrinsic pontine glioma, H3K27M mutation, histone H3.3, H3K27me3, polycomb repressive complex 2, EZH2, histone methylation, gain-of-function mutations, epigenetic regulation
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Animals, Brain Neoplasms, Child, Glioblastoma, Histones, Humans, Lysine, Methionine, Methylation, Transgenes, Amino Acid Substitution, Mutation, Missense, Epigenesis, Genetic, Mice, HEK293 Cells, Polycomb Repressive Complex 2
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