Histone H3.3 Mutations: A Variant Path to Cancer
2013; Cell Press; Volume: 24; Issue: 5 Linguagem: Inglês
10.1016/j.ccr.2013.09.015
ISSN1878-3686
AutoresBenjamin T. K. Yuen, Paul S. Knoepfler,
Tópico(s)Genomics and Chromatin Dynamics
ResumoA host of cancer types exhibit aberrant histone modifications. Recently, distinct and recurrent mutations in a specific histone variant, histone H3.3, have been implicated in a high proportion of malignant pediatric brain cancers. The presence of mutant H3.3 histone disrupts epigenetic posttranslational modifications near genes involved in cancer processes and in brain function. Here, we review possible mechanisms by which mutant H3.3 histones may act to promote tumorigenesis. Furthermore, we discuss how perturbations in normal H3.3 chromatin-related and epigenetic functions may more broadly contribute to the formation of human cancers. A host of cancer types exhibit aberrant histone modifications. Recently, distinct and recurrent mutations in a specific histone variant, histone H3.3, have been implicated in a high proportion of malignant pediatric brain cancers. The presence of mutant H3.3 histone disrupts epigenetic posttranslational modifications near genes involved in cancer processes and in brain function. Here, we review possible mechanisms by which mutant H3.3 histones may act to promote tumorigenesis. Furthermore, we discuss how perturbations in normal H3.3 chromatin-related and epigenetic functions may more broadly contribute to the formation of human cancers. Histones are linked to the genesis of a multitude of cancers primarily through alterations in their posttranslational modification (PTM) and the epigenetic machinery controlling these modifications. Recurrent mutations in histone-modifying enzymes and chromatin remodelers are apparent in various cancer types (Dawson and Kouzarides, 2012Dawson M.A. Kouzarides T. Cancer epigenetics: from mechanism to therapy.Cell. 2012; 150: 12-27Abstract Full Text Full Text PDF PubMed Scopus (2065) Google Scholar), and a number of studies have together provided growing insight into the interplay among histone-modifying enzymes, specific histone PTMs, and tumorigenesis (Suvà et al., 2013Suvà M.L. Riggi N. Bernstein B.E. Epigenetic reprogramming in cancer.Science. 2013; 339: 1567-1570Crossref PubMed Scopus (529) Google Scholar). Emerging lines of investigation are focused on cancer-related mutations in histones themselves as recent studies estimate that 30%–40% of sequenced glioblastoma multiforme (GBM) tumors contain some disruption in epigenetic regulatory machinery, with roughly 11% of all samples bearing specific and recurring histone mutations (Sturm et al., 2012Sturm D. Witt H. Hovestadt V. Khuong-Quang D.A. Jones D.T. Konermann C. Pfaff E. Tönjes M. Sill M. 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Chromatin environment of histone variant H3.3 revealed by quantitative imaging and genome-scale chromatin and DNA immunoprecipitation.Mol. Biol. Cell. 2010; 21: 1872-1884Crossref PubMed Scopus (41) Google Scholar)—in addition to pericentromeric and telomeric regions (Szenker et al., 2011Szenker E. Ray-Gallet D. Almouzni G. The double face of the histone variant H3.3.Cell Res. 2011; 21: 421-434Crossref PubMed Scopus (265) Google Scholar). H3.3 comprises approximately 25% of the total pool of H3 histones in Drosophila melanogaster (Sakai et al., 2009Sakai A. Schwartz B.E. Goldstein S. Ahmad K. Transcriptional and developmental functions of the H3.3 histone variant in Drosophila.Curr. Biol. 2009; 19: 1816-1820Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar) and is found at comparable levels in Mus musculus (Bush et al., 2013Bush K.M. Yuen B.T. Barrilleaux B.L. Riggs J.W. O’Geen H. Cotterman R.F. Knoepfler P.S. Endogenous mammalian histone H3.3 exhibits chromatin-related functions during development.Epigenetics Chromatin. 2013; 6: 7Crossref PubMed Scopus (63) Google Scholar). Two major histone chaperone complexes have been identified as responsible for H3.3 incorporation: histone regulator A (HIRA), which incorporates H3.3 into genic, euchromatic regions in a replication-independent manner (Goldberg et al., 2010Goldberg A.D. Banaszynski L.A. Noh K.M. Lewis P.W. Elsaesser S.J. Stadler S. Dewell S. Law M. Guo X. Li X. et al.Distinct factors control histone variant H3.3 localization at specific genomic regions.Cell. 2010; 140: 678-691Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar, Tagami et al., 2004Tagami H. Ray-Gallet D. Almouzni G. Nakatani Y. 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Thus, the interplay between ATRX/DAXX and H3.3 histones may represent a critical, yet unexplored, axis leading to pediatric gliomas. Loss-of-function studies for genes encoding H3.3 have also proven insightful. Individual homozygous disruption of His3.3A and His3.3B in Drosophila (orthologs of human H3F3A and H3F3B) has little phenotypic effect on the overall organism. In contrast, combined disruption of both genes results in reduced viability and sterility (Hödl and Basler, 2009Hödl M. Basler K. Transcription in the absence of histone H3.3.Curr. Biol. 2009; 19: 1221-1226Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, Sakai et al., 2009Sakai A. Schwartz B.E. Goldstein S. Ahmad K. Transcriptional and developmental functions of the H3.3 histone variant in Drosophila.Curr. Biol. 2009; 19: 1816-1820Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). H3.3 may be necessary to sustain transcription of genes involved in differentiation, as knockdown of H3.3 by morpholino in Xenopus laevis leads to defects in late gastrulation developmental programs (Szenker et al., 2012Szenker E. Lacoste N. Almouzni G. A developmental requirement for HIRA-dependent H3.3 deposition revealed at gastrulation in Xenopus.Cell Rep. 2012; 1: 730-740Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar), and the introduction of a dominant-negative form of H3.3 in zebrafish disrupts neural crest development (Cox et al., 2012Cox S.G. Kim H. Garnett A.T. Medeiros D.M. An W. Crump J.G. An essential role of variant histone H3.3 for ectomesenchyme potential of the cranial neural crest.PLoS Genet. 2012; 8: e1002938Crossref PubMed Scopus (43) Google Scholar). Loss-of-function studies of H3.3 in mammals have only disrupted one of the two H3.3-encoding genes successfully in mice (Bush et al., 2013Bush K.M. Yuen B.T. Barrilleaux B.L. Riggs J.W. O’Geen H. 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At the chromatin level, loss of H3.3 in Drosophila results in a compensatory gap-filling mechanism, whereby HIRA and XNP (the Drosophila ATRX homolog) are bound to previously H3.3-associated regions (Schneiderman et al., 2012Schneiderman J.I. Orsi G.A. Hughes K.T. Loppin B. Ahmad K. Nucleosome-depleted chromatin gaps recruit assembly factors for the H3.3 histone variant.Proc. Natl. Acad. Sci. USA. 2012; 109: 19721-19726Crossref PubMed Scopus (69) Google Scholar). In the mouse, H3.3 acts as a placeholder for CENP-A during cell division (Dunleavy et al., 2011Dunleavy E.M. Almouzni G. Karpen G.H. H3.3 is deposited at centromeres in S phase as a placeholder for newly assembled CENP-A in G1 phase.Nucleus. 2011; 2: 146-157Crossref PubMed Scopus (163) Google Scholar), and partial loss-of-function of H3.3 via knockout of H3f3b causes ectopic CENP-A foci formation (Bush et al., 2013Bush K.M. Yuen B.T. Barrilleaux B.L. Riggs J.W. O’Geen H. Cotterman R.F. Knoepfler P.S. Endogenous mammalian histone H3.3 exhibits chromatin-related functions during development.Epigenetics Chromatin. 2013; 6: 7Crossref PubMed Scopus (63) Google Scholar), with CENP-A acting in a possible compensatory gap-filling mechanism for lost H3.3. Partial loss of H3.3 in Mus also results in defects in cell cycling as well as chromosomal and karyotypic abnormalities (Bush et al., 2013Bush K.M. Yuen B.T. Barrilleaux B.L. Riggs J.W. O’Geen H. Cotterman R.F. Knoepfler P.S. Endogenous mammalian histone H3.3 exhibits chromatin-related functions during development.Epigenetics Chromatin. 2013; 6: 7Crossref PubMed Scopus (63) Google Scholar). Similarly, knockdown of H3.3 leads to embryonic developmental arrest, chromosome missegregation, and chromatin condensation (Lin et al., 2013Lin C.J. Conti M. Ramalho-Santos M. Histone variant H3.3 maintains a decondensed chromatin state essential for mouse preimplantation development.Development. 2013; 140: 3624-3634Crossref PubMed Scopus (86) Google Scholar). Collectively, these data suggest that H3.3 may be necessary for proper chromosome segregation. These studies have also provided insight into the normal function of endogenous H3.3 in the genome and have raised additional possibilities of what goes awry with H3.3 mutations in cancer. How might H3.3 influence epigenetic states? Studies in Drosophila found that only specific residues in place of lysine 4 (a K4 arginine replacement, but not K4 alanine) could restore defects in fertility upon H3.3 removal (Hödl and Basler, 2009Hödl M. Basler K. Transcription in the absence of histone H3.3.Curr. Biol. 2009; 19: 1221-1226Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, Sakai et al., 2009Sakai A. Schwartz B.E. Goldstein S. Ahmad K. Transcriptional and developmental functions of the H3.3 histone variant in Drosophila.Curr. Biol. 2009; 19: 1816-1820Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar), suggesting that the incorporation of a specific PTM, and not just the histone itself, is necessary for proper germ cell function. In Xenopus, H3.3 overexpression augmented an embryo’s memory of the transcriptional state of donor nuclei genes following nuclear transfer to an enucleated egg (Ng and Gurdon, 2008Ng R.K. Gurdon J.B. Epigenetic memory of an active gene state depends on histone H3.3 incorporation into chromatin in the absence of transcription.Nat. Cell Biol. 2008; 10: 102-109Crossref PubMed Scopus (255) Google Scholar). H3.3 was heavily incorporated into regions exhibiting this epigenetic memory. When K4 of H3.3 was replaced with glutamic acid [K4E], incorporation of K4E effectively silenced regions that were previously transcriptionally active (Ng and Gurdon, 2008Ng R.K. Gurdon J.B. 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In Mus, exploration of mutations on the N-terminal tail of H3.3 revealed that incorporation of a lysine 27 to arginine [K27R] mutant form of H3.3 (and not canonical H3.1) in zygotes altered embryonic stage-specific development, caused nuclear segregation abnormalities, and decreased H3K27me3 levels by approximately 65% (Santenard et al., 2010Santenard A. Ziegler-Birling C. Koch M. Tora L. Bannister A.J. Torres-Padilla M.E. Heterochromatin formation in the mouse embryo requires critical residues of the histone variant H3.3.Nat. Cell Biol. 2010; 12: 853-862Crossref PubMed Scopus (222) Google Scholar). The same H3.3 mutation was not found in pediatric gliomas (K27R instead of a lysine 27 to methionine [K27M] substitution), but the data nonetheless demonstrate the adverse consequences from continuous incorporation of K27-mutated H3.3 histone. One such consequence is a failure to establish or delineate proper heterochromatic regions. Finally, recent studies in Xenopus have established that H3.3 and HIRA are necessary to reprogram a nucleus from one transcriptional state to another (Jullien et al., 2012Jullien J. Astrand C. Szenker E. Garrett N. Almouzni G. Gurdon J.B. HIRA dependent H3.3 deposition is required for transcriptional reprogramming following nuclear transfer to Xenopus oocytes.Epigenetics Chromatin. 2012; 5: 17Crossref PubMed Scopus (83) Google Scholar). Thus, H3.3 appears to play a major role in transcriptional plasticity. Reprogramming somatic cells to produce induced pluripotent stem cells has some parallels to tumorigenesis, particularly in regard to the transcriptional programs activated (Riggs et al., 2013Riggs J.W. Barrilleaux B.L. Varlakhanova N. Bush K.M. Chan V. Knoepfler P.S. Induced pluripotency and oncogenic transformation are related processes.Stem Cells Dev. 2013; 22: 37-50Crossref PubMed Scopus (85) Google Scholar, Suvà et al., 2013Suvà M.L. Riggi N. Bernstein B.E. Epigenetic reprogramming in cancer.Science. 2013; 339: 1567-1570Crossref PubMed Scopus (529) Google Scholar). The transcriptional plasticity function of H3.3 may be needed to activate genes during oncogenic transformation as it is needed for maintaining transcriptional memory (Ng and Gurdon, 2008Ng R.K. Gurdon J.B. Epigenetic memory of an active gene state depends on histone H3.3 incorporation into chromatin in the absence of transcription.Nat. Cell Biol. 2008; 10: 102-109Crossref PubMed Scopus (255) Google Scholar) or for switching transcriptional states (Jullien et al., 2012Jullien J. Astrand C. Szenker E. Garrett N. Almouzni G. Gurdon J.B. HIRA dependent H3.3 deposition is required for transcriptional reprogramming following nuclear transfer to Xenopus oocytes.Epigenetics Chromatin. 2012; 5: 17Crossref PubMed Scopus (83) Google Scholar). It remains to be seen what role H3.3 may play in early oncogenic processes. All reported H3.3 mutations identified in human tumors have been in the H3F3A gene leading to single codon changes within the N-terminal tail of the H3.3 protein, a region enriched in PTMs. The first studies identified mutations encoding a K27M substitution in addition to a smaller number of mutations encoding a glycine 34 to arginine or valine [G34R/V] substitution (Schwartzentruber et al., 2012Schwartzentruber J. Korshunov A. Liu X.Y. Jones D.T. Pfaff E. Jacob K. Sturm D. Fontebasso A.M. Quang D.A. Tönjes M. et al.Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.Nature. 2012; 482: 226-231Crossref PubMed Scopus (1707) Google Scholar, Wu et al., 2012Wu G. Broniscer A. McEachron T.A. Lu C. Paugh B.S. Becksfort J. Qu C. Ding L. Huether R. Parker M. et al.St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome ProjectSomatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas.Nat. Genet. 2012; 44: 251-253Crossref PubMed Scopus (1094) Google Scholar). Relatively fewer gliomas exhibited K27M substitutions in HIST1H3B, one gene of several encoding canonical H3.1 histone; interestingly, H3.1 mutations appear to be restricted to DIPG and non-brainstem pediatric GBM in a younger range of patients (median = 4.75 years; Wu et al., 2012Wu G. Broniscer A. McEachron T.A. Lu C. Paugh B.S. Becksfort J. Qu C. Ding L. Huether R. Pa
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