Abstract
Mono-ubiquitinated histone H2B (H2B-Ub) is important for chromatin regulation of transcription, chromatin assembly, and also influences heterochromatin. In this review, we discuss the effects of H2B-Ub from nucleosome to higher-order chromatin structure. We then assess what is currently known of the role of H2B-Ub in heterochromatic silencing in budding and fission yeasts (S. cerevisiae and S. pombe), which have distinct silencing mechanisms. In budding yeast, the SIR complex initiates heterochromatin assembly with the aid of a H2B-Ub deubiquitinase, Ubp10. In fission yeast, the RNAi-dependent pathway initiates heterochromatin in the context of low H2B-Ub. We examine how the different silencing machineries overcome the challenge of H2B-Ub chromatin and highlight the importance of using these microorganisms to further our understanding of H2B-Ub in heterochromatic silencing pathways.
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References
Alvarez V, Vinas L, Gallego-Sanchez A, Andres S, Sacristan MP, Bueno A (2016) Orderly progression through S-phase requires dynamic ubiquitylation and deubiquitylation of. PCNA Sci Rep 6:25513. https://doi.org/10.1038/srep25513
Armache KJ, Garlick JD, Canzio D, Narlikar GJ, Kingston RE (2011) Structural basis of silencing: Sir3 BAH domain in complex with a nucleosome at 3.0 A resolution. Science 334:977–982. https://doi.org/10.1126/science.1210915
Batta K, Zhang Z, Yen K, Goffman DB, Pugh BF (2011) Genome-wide function of H2B ubiquitylation in promoter and genic regions. Genes Dev 25:2254–2265. https://doi.org/10.1101/gad.177238.111
Behrouzi R, Lu C, Currie MA, Jih G, Iglesias N, Moazed D (2016) Heterochromatin assembly by interrupted Sir3 bridges across neighboring nucleosomes. Elife. https://doi.org/10.7554/eLife.17556
Briggs SD et al (2002) Gene silencing: trans-histone regulatory pathway in chromatin. Nature 418:498. https://doi.org/10.1038/nature00970
Chandrasekharan MB, Huang F, Sun ZW (2009) Ubiquitination of histone H2B regulates chromatin dynamics by enhancing nucleosome stability. Proc Natl Acad Sci USA 106:16686–16691. https://doi.org/10.1073/pnas.0907862106
Choi ES, Kim HS, Jang YK, Hong SH, Park SD (2002) Two ubiquitin-conjugating enzymes, Rhp6 and UbcX, regulate heterochromatin silencing in Schizosaccharomyces pombe. Mol Cell Biol 22:8366–8374
D’Urso A, Brickner JH (2017) Epigenetic transcriptional memory. Curr Genet 63:435–439. https://doi.org/10.1007/s00294-016-0661-8
Debelouchina GT, Gerecht K, Muir TW (2017) Ubiquitin utilizes an acidic surface patch to alter chromatin structure. Nat Chem Biol 13:105–110. https://doi.org/10.1038/nchembio.2235
Ehrentraut S et al (2011) Structural basis for the role of the Sir3 AAA+ domain in silencing: interaction with Sir4 and unmethylated histone H3K79. Genes Dev 25:1835–1846. https://doi.org/10.1101/gad.17175111
Emre NC et al (2005) Maintenance of low histone ubiquitylation by Ubp10 correlates with telomere-proximal Sir2 association and gene silencing. Mol Cell 17:585–594. https://doi.org/10.1016/j.molcel.2005.01.007
Fierz B, Chatterjee C, McGinty RK, Bar-Dagan M, Raleigh DP, Muir TW (2011) Histone H2B ubiquitylation disrupts local and higher-order chromatin compaction. Nat Chem Biol 7:113–119. https://doi.org/10.1038/nchembio.501
Fleming AB, Kao CF, Hillyer C, Pikaart M, Osley MA (2008) H2B ubiquitylation plays a role in nucleosome dynamics during transcription elongation. Mol Cell 31:57–66. https://doi.org/10.1016/j.molcel.2008.04.025
Flury V, Georgescu PR, Iesmantavicius V, Shimada Y, Kuzdere T, Braun S, Buhler M (2017) The histone acetyltransferase Mst2 protects active chromatin from epigenetic silencing by acetylating the ubiquitin ligase Brl1. Mol Cell 67:294.e299–307.e299. https://doi.org/10.1016/j.molcel.2017.05.026
Gallego-Sanchez A, Andres S, Conde F, San-Segundo PA, Bueno A (2012) Reversal of PCNA ubiquitylation by Ubp10 in Saccharomyces cerevisiae. PLoS Genet 8:e1002826. https://doi.org/10.1371/journal.pgen.1002826
Gardner RG, Nelson ZW, Gottschling DE (2005) Ubp10/Dot4p regulates the persistence of ubiquitinated histone H2B: distinct roles in telomeric silencing and general chromatin. Mol Cell Biol 25:6123–6139. https://doi.org/10.1128/MCB.25.14.6123-6139.2005
Hecht A, Laroche T, Strahl-Bolsinger S, Gasser SM, Grunstein M (1995) Histone H3 and H4 N-termini interact with SIR3 and SIR4 proteins: a molecular model for the formation of heterochromatin in yeast. Cell 80:583–592
Henry KW et al (2003) Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8. Genes Dev 17:2648–2663. https://doi.org/10.1101/gad.1144003
Johnson A, Li G, Sikorski TW, Buratowski S, Woodcock CL, Moazed D (2009) Reconstitution of heterochromatin-dependent transcriptional gene silencing. Mol Cell 35:769–781. https://doi.org/10.1016/j.molcel.2009.07.030
Kahana A, Gottschling DE (1999) DOT4 links silencing and cell growth in Saccharomyces cerevisiae. Mol Cell Biol 19:6608–6620
Katan-Khaykovich Y, Struhl K (2005) Heterochromatin formation involves changes in histone modifications over multiple cell generations. EMBO J 24:2138–2149. https://doi.org/10.1038/sj.emboj.7600692
Kitada T, Kuryan BG, Tran NN, Song C, Xue Y, Carey M, Grunstein M (2012) Mechanism for epigenetic variegation of gene expression at yeast telomeric heterochromatin. Genes Dev 26:2443–2455. https://doi.org/10.1101/gad.201095.112
Komander D, Clague MJ, Urbe S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10:550–563. https://doi.org/10.1038/nrm2731
Kouranti I, McLean JR, Feoktistova A, Liang P, Johnson AE, Roberts-Galbraith RH, Gould KL (2010) A global census of fission yeast deubiquitinating enzyme localization and interaction networks reveals distinct compartmentalization profiles and overlapping functions in endocytosis and polarity. PLoS Biol. https://doi.org/10.1371/journal.pbio.1000471
Kowalik KM, Shimada Y, Flury V, Stadler MB, Batki J, Buhler M (2015) The Paf1 complex represses small-RNA-mediated epigenetic gene silencing. Nature 520:248–252. https://doi.org/10.1038/nature14337
Kueng S, Oppikofer M, Gasser SM (2013) SIR proteins and the assembly of silent chromatin in budding yeast. Annu Rev Genet 47:275–306. https://doi.org/10.1146/annurev-genet-021313-173730
Larin ML et al (2015) Competition between heterochromatic loci allows the abundance of the silencing protein, Sir4, to regulate de novo assembly of heterochromatin. PLoS Genet 11:e1005425. https://doi.org/10.1371/journal.pgen.1005425
Lee KK, Florens L, Swanson SK, Washburn MP, Workman JL (2005) The deubiquitylation activity of Ubp8 is dependent upon Sgf11 and its association with the SAGA complex. Mol Cell Biol 25:1173–1182. https://doi.org/10.1128/MCB.25.3.1173-1182.2005
Luke B, Lingner J (2009) TERRA: telomeric repeat-containing RNA. EMBO J 28:2503–2510. https://doi.org/10.1038/emboj.2009.166
Machida S, Sekine S, Nishiyama Y, Horikoshi N, Kurumizaka H (2016) Structural and biochemical analyses of monoubiquitinated human histones H2B and H4. Open Biol. https://doi.org/10.1098/rsob.160090
Martienssen R, Moazed D (2015) RNAi and heterochromatin assembly. Cold Spring Harb Perspect Biol 7:a019323. https://doi.org/10.1101/cshperspect.a019323
Miles S, Breeden L (2017) A common strategy for initiating the transition from proliferation to quiescence. Curr Genet 63:179–186. https://doi.org/10.1007/s00294-016-0640-0
Morgan MT, Haj-Yahya M, Ringel AE, Bandi P, Brik A, Wolberger C (2016) Structural basis for histone H2B deubiquitination by the SAGA DUB module. Science 351:725–728. https://doi.org/10.1126/science.aac5681
Mueller CL, Jaehning JA (2002) Ctr9, Rtf1, and Leo1 are components of the Paf1/RNA polymerase II complex. Mol Cell Biol 22:1971–1980
Ng HH, Ciccone DN, Morshead KB, Oettinger MA, Struhl K (2003a) Lysine-79 of histone H3 is hypomethylated at silenced loci in yeast and mammalian cells: a potential mechanism for position-effect variegation. Proc Natl Acad Sci USA 100:1820–1825. https://doi.org/10.1073/pnas.0437846100
Ng HH, Robert F, Young RA, Struhl K (2003b) Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional Activity. Mol Cell 11:709–719. https://doi.org/10.1016/s1097-2765(03)00092-3
Onishi M, Liou GG, Buchberger JR, Walz T, Moazed D (2007) Role of the conserved Sir3-BAH domain in nucleosome binding and silent chromatin. assembly. Mol Cell 28:1015–1028. https://doi.org/10.1016/j.molcel.2007.12.004
Oppikofer M et al (2011) A dual role of H4K16 acetylation in the establishment of yeast silent chromatin. EMBO J 30:2610–2621. https://doi.org/10.1038/emboj.2011.170
Oppikofer M, Kueng S, Gasser SM (2013) SIR-nucleosome interactions: structure-function relationships in yeast silent chromatin. Gene 527:10–25. https://doi.org/10.1016/j.gene.2013.05.088
Orlandi I, Bettiga M, Alberghina L, Vai M (2004) Transcriptional profiling of ubp10 null mutant reveals altered subtelomeric gene expression and insurgence of oxidative stress response. J Biol Chem 279:6414–6425. https://doi.org/10.1074/jbc.M306464200
Osborne EA, Dudoit S, Rine J (2009) The establishment of gene silencing at single-cell resolution. Nat Genet 41:800–806. https://doi.org/10.1038/ng.402
Pavri R, Zhu B, Li G, Trojer P, Mandal S, Shilatifard A, Reinberg D (2006) Histone H2B monoubiquitination functions cooperatively with FACT to regulate elongation by RNA polymerase II. Cell 125:703–717. https://doi.org/10.1016/j.cell.2006.04.029
Racine A, Page V, Nagy S, Grabowski D, Tanny JC (2012) Histone H2B ubiquitylation promotes activity of the intact Set1 histone methyltransferase complex in fission yeast. J Biol Chem 287:19040–19047. https://doi.org/10.1074/jbc.M112.356253
Reed BJ, Locke MN, Gardner RG (2015) A conserved deubiquitinating enzyme uses intrinsically disordered regions to scaffold multiple protein interaction sites. J Biol Chem 290:20601–20612. https://doi.org/10.1074/jbc.M115.650952
Rhie BH, Song YH, Ryu HY, Ahn SH (2013) Cellular aging is associated with increased ubiquitylation of histone H2B in yeast telomeric heterochromatin Biochem. Biophys Res Commun 439:570–575. https://doi.org/10.1016/j.bbrc.2013.09.017
Richardson LA et al (2012) A conserved deubiquitinating enzyme controls cell growth by regulating RNA polymerase I stability. Cell Rep 2:372–385. https://doi.org/10.1016/j.celrep.2012.07.009
Robzyk K, Recht J, Osley MA (2000) Rad6-dependent ubiquitination of histone H2B yeast. Science 287:501–504
Sadeghi L, Prasad P, Ekwall K, Cohen A, Svensson JP (2015) The Paf1 complex factors Leo1 and Paf1 promote local histone turnover to modulate chromatin states in fission yeast. EMBO Rep 16:1673–1687. https://doi.org/10.15252/embr.201541214
Sahtoe DD, Sixma TK (2015) Layers of DUB regulation. Trends Biochem Sci 40:456–467. https://doi.org/10.1016/j.tibs.2015.05.002
Santos-Rosa H, Bannister AJ, Dehe PM, Geli V, Kouzarides T (2004) Methylation of H3 lysine 4 at euchromatin promotes Sir3p association with heterochromatin. J Biol Chem 279:47506–47512. https://doi.org/10.1074/jbc.M407949200
Schulze JM, Hentrich T, Nakanishi S, Gupta A, Emberly E, Shilatifard A, Kobor MS (2011) Splitting the task: Ubp8 and Ubp10 deubiquitinate different cellular pools of H2BK123. Genes Dev 25:2242–2247. https://doi.org/10.1101/gad.177220.111
Segala G, Bennesch MA, Pandey DP, Hulo N, Picard D (2016) Monoubiquitination of histone H2B blocks eviction of histone variant H2A.Z from inducible enhancers. Mol Cell 64:334–346. https://doi.org/10.1016/j.molcel.2016.08.034
Shahbazian MD, Zhang K, Grunstein M (2005) Histone H2B ubiquitylation controls processive methylation but not monomethylation by Dot1 and Set1. Mol Cell 19:271–277. https://doi.org/10.1016/j.molcel.2005.06.010
Shimada Y, Mohn F, Buhler M (2016) The RNA-induced transcriptional silencing complex targets chromatin exclusively via interacting with nascent transcripts. Genes Dev 30:2571–2580. https://doi.org/10.1101/gad.292599.116
Singer MS et al (1998) Identification of high-copy disruptors of telomeric silencing in Saccharomyces cerevisiae. Genetics 150:613–632
Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45. https://doi.org/10.1038/47412
Suganuma T, Workman JL (2011) Signals and combinatorial functions of histone modifications. Annu Rev Biochem 80:473–499. https://doi.org/10.1146/annurev-biochem-061809-175347
Sun ZW, Allis CD (2002) Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature 418:104–108. https://doi.org/10.1038/nature00883
Tanny JC, Erdjument-Bromage H, Tempst P, Allis CD (2007) Ubiquitylation of histone H2B controls RNA polymerase II transcription elongation independently of histone H3 methylation. Genes Dev 21:835–847. https://doi.org/10.1101/gad.1516207
Trujillo KM, Osley MA (2012) A role for H2B ubiquitylation in DNA replication. Mol Cell 48:734–746. https://doi.org/10.1016/j.molcel.2012.09.019
van Leeuwen F, Gafken PR, Gottschling DE (2002) Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109:745–756
Van Oss SB et al (2016) The histone modification domain of Paf1 complex subunit Rtf1 directly stimulates H2B ubiquitylation through an interaction with Rad6. Mol Cell 64:815–825. https://doi.org/10.1016/j.molcel.2016.10.008
Vlaming H et al (2014) Flexibility in crosstalk between H2B ubiquitination and H3 methylation in vivo. EMBO Rep 15:1077–1084. https://doi.org/10.15252/embr.201438793
Wan Y, Chiang JH, Lin CH, Arens CE, Saleem RA, Smith JJ, Aitchison JD (2010) Histone chaperone Chz1p regulates H2B ubiquitination and subtelomeric anti-silencing. Nucleic Acids Res 38:1431–1440. https://doi.org/10.1093/nar/gkp1099
Wang F, Li G, Altaf M, Lu C, Currie MA, Johnson A, Moazed D (2013) Heterochromatin protein Sir3 induces contacts between the amino terminus of histone H4 and nucleosomal DNA. Proc Natl Acad Sci USA 110:8495–8500. https://doi.org/10.1073/pnas.1300126110
Wood A, Schneider J, Dover J, Johnston M, Shilatifard A (2003) The Paf1 complex is essential for histone monoubiquitination by the Rad6–Bre1 complex, which signals for histone methylation by COMPASS and Dot1p. J Biol Chem 278:34739–34742. https://doi.org/10.1074/jbc.C300269200
Wu MY, Lin CY, Tseng HY, Hsu FM, Chen PY, Kao CF (2017) H2B ubiquitylation and the histone chaperone Asf1 cooperatively mediate the formation and maintenance of heterochromatin silencing. Nucleic Acids Res 45:8225–8238. https://doi.org/10.1093/nar/gkx422
Zofall M, Grewal SI (2007) HULC, a histone H2B ubiquitinating complex, modulates heterochromatin independent of histone methylation in fission yeast. J Biol Chem 282:14065–14072. https://doi.org/10.1074/jbc.M700292200
Zukowski A, Al-Afaleq NO, Duncan ED, Yao T, Johnson AM (2017) Recruitment and allosteric stimulation of a histone deubiquitinating enzyme during heterochromatin assembly. J Biol Chem. https://doi.org/10.1074/jbc.RA117.000498
Acknowledgements
We would like to thank T. Yao for helpful discussions, and E. Duncan and R. Ancar for feedback with this manuscript. This work was supported by NIH Grants T32GM008730 (A. Z.) and R35GM119575 (A. M. J).
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Zukowski, A., Johnson, A.M. The interplay of histone H2B ubiquitination with budding and fission yeast heterochromatin. Curr Genet 64, 799–806 (2018). https://doi.org/10.1007/s00294-018-0812-1
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DOI: https://doi.org/10.1007/s00294-018-0812-1