CELL CYCLE 2016, VOL. 15, NO. 16, 2093–2094 http://dx.doi.org/10.1080/15384101.2016.1191248

EDITORIALS: CELL CYCLE FEATURES

Global chromatin architecture defines functional cancer hierarchies Marco Galloa and Peter B. Dirksb,c a

Department of Physiology and Pharmacology, Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; bDevelopmental and Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON, Canada; cDepartment of Molecular Genetics, Department of Laboratory Medicine and Pathobiology, Division of Neurosurgery, University of Toronto, Toronto, ON, Canada ARTICLE HISTORY Received 3 April 2016; Revised 6 May 2016; Accepted 10 May 2016

In the realm of the mutational landscape of brain malignancies, a paradigm-shifting discovery occurred in 2012 with the identification of recurrent mutations in the histone 3 variant H3.3.1 These mutations affected a third of pediatric gliomas and always occur at lysine 27 (K27) or glycine 34 (G34) of H3.3. Histones are the protein constituents of the nucleosome, whose role is to maintain proper chromatin compaction in the nucleus. The nucleosome is composed of a short stretch of DNA and four core histone proteins: H2A, H2B, H3 and H4. Each core histone exists in several variants, with the exception of H4. Mutations in H3.3 were surprising because, for the first time, they implied an active, functional role for the nucleosome in cancer biology and etiology, beside for its DNA scaffolding function. In addition to a better appreciation of the role of chromatin remodellers in cancer, mutations in this histone variant stressed the importance of overall chromatin architecture for cancer biology. This hypothesis was supported by multiple lines of evidence. First, H3.3K27M mutations cause a global decrease in the levels of H3K27me3,2 which is a repressive chromatin mark associated with decreased gene transcription. Second, tumors with either H3.3K27 or H3.3G34 mutations have very characteristic DNA methylation profiles,3 features also associated with chromatin compaction. Mutations in H3.3 are not exclusive to pediatric brain tumors. They have been identified in other solid tumors, including osteosarcoma, giant cell tumor of bone, conventional and clear cell chondrosarcomas, and chondroblastoma,4 some of which occur more frequently in young patients. The selection for H3.3 mutations in multiple cancers suggests that H3.3 itself, and therefore the nucleosome, may play an important role in the etiology of cancers. However, the exact role of wild-type H3.3 in cancer cells was not known until recently. Furthermore, mutations in H3.3 in adult GBM patients are very rare and usually confined to younger individuals in their early twenties. We have recently reported that H3.3 is epigenetically repressed in the cancer stem cell (CSC) population of adult

GBM.5 We found that the chromatin remodeller MLL5 is responsible for this repression. As cells become more “differentiated” and lose their self-renewal and tumor-initiating characteristics, they decrease the levels of MLL5, which results in derepression of H3.3. Therefore, our data showed that H3.3 has a role in suppressing CSC properties, which are fundamental for tumor propagation and recurrence in this hierarchically organized malignancy. Although MLL5 is expressed in a subset of fetal neural stem cells, we found that its function here was decoupled from repression of H3.3. It is therefore possible that this function of MLL5 is context-dependent. Interestingly, the role of H3.3 in adult GBM parallels its function in normal brain development. Recent work has shown that H3.3 accumulates in mouse neurons with age, as well as in the human brain, whereas the other major histone 3 variants H3.1 and H3.2 decline.6 The authors also showed that appropriately high expression of H3.3 is required for proper neuronal function, such as synapse formation.6 We propose that H3.3 repression in GBM CSCs is consistent with achieving a brainspecific primordial state that allows self-renewal and tumor propagation. We also noted that global levels of H3K4me3, a marker of active transcription, were severely decreased in GBM CSCs with low H3.3 levels. These findings are consistent with H3.3 being the principal histone 3 variant carrying the K4me3 modification. Of note, a recent report showed that the requirements for H3K4me3 may be the opposite in the leukemic hierarchy, where H3K4me3 levels are high in the leukemic stem cells and decreases with their differentiation.7 It would be interesting to investigate whether the levels of H3.3 are also dynamically regulated in the leukemic hierarchy, and if this histone variant is a proxy for H3K4me3 levels, as is the case for GBM. Since we found that the levels of H3.3 and H3K4me3 are tightly tied to each other, we hypothesize that the leukemic hierarchy is also inverted compared to GBM, with the

CONTACT Marco Gallo [email protected] 3330 Hospital Drive NW, HRIC Rm 2A08, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N [email protected] Division of Neurosurgery, Hospital for Sick Children, Suite 1503, 555 University Ave., Toronto, Ontario, Canada, 4N1, Canada; Dr. Peter B. Dirks M5G 1X8. Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/kccy. Feature to: Gallo M, et al. MLL5 orchestrates a cancer self-renewal state by repressing the histone variant H3.3 and globally reorganizing chromatin. Cancer Cell 2015; 28 (6):715-29; PMID: 26626085; http://dx.doi.org/10.1016/j.ccell.2015.10.005. © 2016 Taylor & Francis

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further validation for the use of compounds that target chromatin remodellers (epidrugs) as next-generation therapeutics. This strategy is attractive as these studies demonstrate that altering chromatin compaction can change the functional behavior of a cell, likely by reversing entire transcriptional programs that are primarily associated with the CSC state. If deployed rationally, epidrugs may not simply be blunt tools to repress or de-repress global transcription, but rather they may act surgically to reprogram chromatin organization and push a cell into a non-CSC state, limiting clonal output and possibly conferring greater sensitivity to conventional therapy that is more effective on these predominant cell types within the tumor.

Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.

References

Figure 1. H3K4me3 levels in cancer hierarchies. Functional hierarchies in adult GBM are characterized by low levels of H3K4me3 in the cancer stem cells, and higher levels in the non-tumor-initiating cells. On the contrary, in the leukemic hierarchy the relative levels of H3K4me3 are higher in the cancer stem cells and lower in the more differentiated cells.

leukemia stem cell having more H3.3 than its differentiated counterparts. In any event, the different roles of H3K4me3 in the GBM and leukemia hierarchies may underlie chromatin configurations that are specific to the tissue - and perhaps cell of origin - of each malignancy (Fig. 1). Based on the paradigm established for GBM and leukemia with respect to H3.3 and H3K4me3, we speculate that strategic chromatin compaction states confer CSC properties in several malignancies. The exact nature of overall chromatin compaction may depend on the tissue where the cancer originates and develops. The idea that chromatin architecture programs cell identity in cancer extends naturally from the identification of differential gene expression signatures between cancer stem cells and their matched non-CSC counterparts. However, the extent of chromatin reorganization in the transition from CSC to non-CSC is impressive because of its large scale as defined by our microscopy experiments, and is unlikely to be confined to discrete regions of the genome that are differentially expressed. The identification of clear chromatin configurations associated with CSC properties in GBM5 and leukemia7 provides

[1] Schwartzentruber J, Korshunov A, Liu X-Y, Jones DTW, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Khuong Quang D-A, T€ onjes M, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012; 482:226-31; PMID:22286061; http://dx.doi.org/10.1038/nature10833 [2] Lewis PW, M€ uller MM, Koletsky MS, Cordero F, Lin S, Banaszynski LA, Garcia BA, Muir TW, Becher OJ, Allis CD. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 2013; 340:857-61; PMID:23539183; http://dx.doi.org/ 10.1126/science.1232245 [3] Sturm D, Witt H, Hovestadt V, Khuong-Quang D-A, Jones DTW, Konermann C, Pfaff E, T€ onjes M, Sill M, Bender S, et al. Hotspot, utations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 2012; 22:425-37; PMID: 23079654; http://dx.doi.org/10.1016/j.ccr.2012.08.024 [4] Behjati S, Tarpey PS, Presneau N, Scheipl S, Pillay N, Van Loo P, Wedge DC, Cooke SL, Gundem G, Davies H, et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet 2013; 45:1479-82; PMID:24162739; http:// dx.doi.org/10.1038/ng.2814 [5] Gallo M, Coutinho FJ, Vanner RJ, Gayden T, Mack SC, Murison A, Remke M, Li R, Takayama N, Desai K, et al. MLL5 orchestrates a cancer self-renewal state by repressing the histone variant H3.3 and globally reorganizing chromatin. Cancer Cell 2015; 28:715-29; PMID: 26626085; http://dx.doi.org/10.1016/j.ccell.2015.10.005 [6] Maze I, Wenderski W, Noh KM, Bagot RC, Tzavaras N, Purushothaman I, Els€asser SJ, Guo Y, Ionete C, Hurd YL, et al. Critical role of histone turnover in neuronal transcription and plasticity. Neuron 2015; 87:77-94; PMID:26139371; http://dx.doi.org/10.1016/j.neuron.2015. 06.014 [7] Wong SH, Goode DL, Iwasaki M, Wei MC, Kuo H-P, Zhu L, Schneidawind D, Duque-Alfonso J, Weng Z, Cleary ML. The H3K4-methyl epigenome regulates leukemia stem cell pncogenic potential. Cancer Cell 2015; 28:198-209; PMID:26190263; http://dx.doi.org/10.1016/j. ccell.2015.06.003

Global chromatin architecture defines functional cancer hierarchies.

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