Current Genetics

, Volume 64, Issue 4, pp 799–806 | Cite as

The interplay of histone H2B ubiquitination with budding and fission yeast heterochromatin

  • Alexis Zukowski
  • Aaron M. JohnsonEmail author


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.


SIR complex Ubp10 Ubiquitination Silencing Heterochromatin Epigenetics 



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).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 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. CrossRefPubMedGoogle Scholar
  2. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Behrouzi R, Lu C, Currie MA, Jih G, Iglesias N, Moazed D (2016) Heterochromatin assembly by interrupted Sir3 bridges across neighboring nucleosomes. Elife. PubMedPubMedCentralCrossRefGoogle Scholar
  5. Briggs SD et al (2002) Gene silencing: trans-histone regulatory pathway in chromatin. Nature 418:498. CrossRefPubMedGoogle Scholar
  6. 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. CrossRefPubMedGoogle Scholar
  7. 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 22:8366–8374CrossRefPubMedPubMedCentralGoogle Scholar
  8. D’Urso A, Brickner JH (2017) Epigenetic transcriptional memory. Curr Genet 63:435–439. CrossRefPubMedGoogle Scholar
  9. Debelouchina GT, Gerecht K, Muir TW (2017) Ubiquitin utilizes an acidic surface patch to alter chromatin structure. Nat Chem Biol 13:105–110. CrossRefPubMedGoogle Scholar
  10. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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. CrossRefPubMedGoogle Scholar
  12. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 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. CrossRefPubMedGoogle Scholar
  14. 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. CrossRefGoogle Scholar
  15. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 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 80:583–592CrossRefPubMedGoogle Scholar
  18. Henry KW et al (2003) Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8. Genes Dev 17:2648–2663. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Kahana A, Gottschling DE (1999) DOT4 links silencing and cell growth in Saccharomyces cerevisiae. Mol Cell Biol 19:6608–6620CrossRefPubMedPubMedCentralGoogle Scholar
  21. Katan-Khaykovich Y, Struhl K (2005) Heterochromatin formation involves changes in histone modifications over multiple cell generations. EMBO J 24:2138–2149. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Komander D, Clague MJ, Urbe S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10:550–563. CrossRefPubMedGoogle Scholar
  24. 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. PubMedPubMedCentralCrossRefGoogle Scholar
  25. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Kueng S, Oppikofer M, Gasser SM (2013) SIR proteins and the assembly of silent chromatin in budding yeast. Annu Rev Genet 47:275–306. CrossRefPubMedGoogle Scholar
  27. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Luke B, Lingner J (2009) TERRA: telomeric repeat-containing RNA. EMBO J 28:2503–2510. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Machida S, Sekine S, Nishiyama Y, Horikoshi N, Kurumizaka H (2016) Structural and biochemical analyses of monoubiquitinated human histones H2B and H4. Open Biol. PubMedPubMedCentralCrossRefGoogle Scholar
  31. Martienssen R, Moazed D (2015) RNAi and heterochromatin assembly. Cold Spring Harb Perspect Biol 7:a019323. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Miles S, Breeden L (2017) A common strategy for initiating the transition from proliferation to quiescence. Curr Genet 63:179–186. CrossRefPubMedGoogle Scholar
  33. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Mueller CL, Jaehning JA (2002) Ctr9, Rtf1, and Leo1 are components of the Paf1/RNA polymerase II complex. Mol Cell Biol 22:1971–1980CrossRefPubMedPubMedCentralGoogle Scholar
  35. 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. CrossRefPubMedGoogle Scholar
  36. 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. CrossRefPubMedGoogle Scholar
  37. 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. CrossRefPubMedGoogle Scholar
  38. Oppikofer M et al (2011) A dual role of H4K16 acetylation in the establishment of yeast silent chromatin. EMBO J 30:2610–2621. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Oppikofer M, Kueng S, Gasser SM (2013) SIR-nucleosome interactions: structure-function relationships in yeast silent chromatin. Gene 527:10–25. CrossRefPubMedGoogle Scholar
  40. 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. CrossRefPubMedGoogle Scholar
  41. Osborne EA, Dudoit S, Rine J (2009) The establishment of gene silencing at single-cell resolution. Nat Genet 41:800–806. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 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. CrossRefPubMedGoogle Scholar
  43. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 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. CrossRefGoogle Scholar
  46. Richardson LA et al (2012) A conserved deubiquitinating enzyme controls cell growth by regulating RNA polymerase I stability. Cell Rep 2:372–385. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Robzyk K, Recht J, Osley MA (2000) Rad6-dependent ubiquitination of histone H2B yeast. Science 287:501–504CrossRefPubMedGoogle Scholar
  48. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Sahtoe DD, Sixma TK (2015) Layers of DUB regulation. Trends Biochem Sci 40:456–467. CrossRefPubMedGoogle Scholar
  50. 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. CrossRefPubMedGoogle Scholar
  51. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 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. CrossRefPubMedGoogle Scholar
  53. 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. CrossRefPubMedGoogle Scholar
  54. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Singer MS et al (1998) Identification of high-copy disruptors of telomeric silencing in Saccharomyces cerevisiae. Genetics 150:613–632PubMedPubMedCentralGoogle Scholar
  56. Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45. CrossRefPubMedGoogle Scholar
  57. Suganuma T, Workman JL (2011) Signals and combinatorial functions of histone modifications. Annu Rev Biochem 80:473–499. CrossRefPubMedGoogle Scholar
  58. Sun ZW, Allis CD (2002) Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature 418:104–108. CrossRefPubMedGoogle Scholar
  59. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  60. Trujillo KM, Osley MA (2012) A role for H2B ubiquitylation in DNA replication. Mol Cell 48:734–746. CrossRefPubMedPubMedCentralGoogle Scholar
  61. van Leeuwen F, Gafken PR, Gottschling DE (2002) Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109:745–756CrossRefPubMedGoogle Scholar
  62. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Vlaming H et al (2014) Flexibility in crosstalk between H2B ubiquitination and H3 methylation in vivo. EMBO Rep 15:1077–1084. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 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. CrossRefPubMedGoogle Scholar
  65. 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. CrossRefPubMedGoogle Scholar
  66. 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. CrossRefPubMedGoogle Scholar
  67. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 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. CrossRefPubMedGoogle Scholar
  69. 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. PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular GeneticsUniversity of Colorado, Denver - School of MedicineAuroraUSA

Personalised recommendations