Chromosome Research

, Volume 14, Issue 1, pp 83–94 | Cite as

Heterochromatin assembly: A new twist on an old model



The organization of eukaryotic genomes requires a harmony between efficient compaction and accessibility. This is achieved through its packaging into chromatin. Chromatin can be subdivided into two general structural and functional compartments: euchromatin and heterochromatin. Euchromatin comprises most of the expressed genome, while heterochromatin participates intimately in the production of structures such as centromeres and telomeres essential for chromosome function. Studies in the fission yeast Schizosaccharomyces pombe have begun to highlight the genetic pathways critical for the assembly and epigenetic maintenance of heterochromatin, including key roles played by the RNAi machinery, H3 lysine 9 methylation and heterochromatin protein 1 (HP1). Recent studies have also identified a novel E3 ubiquitin ligase universally required for H3 K9 methylation. Here we outline these studies and propose several models for the role of this E3 ligase in heterochromatin assembly.

Key words

Clr4 cullin 4 fission yeast heterochromatin Rik1 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Allshire RC, Javerzat JP, Redhead NJ, Cranston G (1994) Position effect variegation at fission yeast centromeres. Cell 76: 157–169.CrossRefPubMedGoogle Scholar
  2. Bernard P, Maure JF, Partridge JF, Genier S, Javerzat JP, Allshire RC (2001) Requirement of heterochromatin for cohesion at centromeres. Science 294: 2539–2542.CrossRefPubMedGoogle Scholar
  3. Cam HP, Sugiyama T, Chen ES, Chen X, Fitzgerald PC, Grewal SI (2005) Comprehensive analysis of heterochromatin- and RNAi-mediated epigenetic control of the fission yeast genome. Nat Genet 37: 809–819.CrossRefPubMedGoogle Scholar
  4. Cardozo T, Pagano M (2004) The SCF ubiquitin ligase: insights into a molecular machine. Nat Rev Mol Cell Biol 5: 739–751.CrossRefPubMedGoogle Scholar
  5. Djupedal I, Portoso M, Spahr H et al. (2005) RNA Pol II subunit Rpb7 promotes centromeric transcription and RNAi-directed chromatin silencing. Genes Dev 19: 2301–2306.CrossRefPubMedGoogle Scholar
  6. Doe CL, Wang G, Chow C, Fricker MD, Singh PB, Mellor EJ (1998) The fission yeast chromo domain encoding gene chp1(+) is required for chromosome segregation and shows a genetic interaction with alpha-tubulin. Nucl Acids Res 26: 4222–4229.CrossRefPubMedGoogle Scholar
  7. Ekwall K, Ruusala T (1994) Mutations in rik1, clr2, clr3 and clr4 genes asymmetrically derepress the silent mating-type loci in fission yeast. Genetics 136: 53–64.PubMedGoogle Scholar
  8. Fischle W, Wang Y, Jacobs SA, Kim Y, Allis CD, Khorasanizadeh S (2003) Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev 17: 1870–1881.CrossRefPubMedGoogle Scholar
  9. Flick K, Ouni I, Wohlschlegel JA et al. (2004) Proteolysis-independent regulation of the transcription factor Met4 by a single Lys 48-linked ubiquitin chain. Nat Cell Biol 6: 634–641.CrossRefPubMedGoogle Scholar
  10. Grewal SI, Elgin SC (2002) Heterochromatin: new possibilities for the inheritance of structure. Curr Opin Genet Dev 12: 178–187.CrossRefPubMedGoogle Scholar
  11. Grewal SI, Klar AJ (1996) Chromosomal inheritance of epigenetic states in fission yeast during mitosis and meiosis. Cell 86: 95–101.CrossRefPubMedGoogle Scholar
  12. Grewal SI, Bonaduce MJ, Klar AJ (1998) Histone deacetylase homologs regulate epigenetic inheritance of transcriptional silencing and chromosome segregation in fission yeast. Genetics 150: 563–576.PubMedGoogle Scholar
  13. Groisman R, Polanowska J, Kuraoka I et al. (2003) The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell 113: 357–367.CrossRefPubMedGoogle Scholar
  14. Hall IM, Shankaranarayana GD, Noma K, Ayoub N, Cohen A, Grewal SI (2002) Establishment and maintenance of a heterochromatin domain. Science 297: 2232–2237.CrossRefPubMedGoogle Scholar
  15. Hall IM, Noma K, Grewal SI (2003) RNA interference machinery regulates chromosome dynamics during mitosis and meiosis in fission yeast. Proc Natl Acad Sci USA 100: 193–198.PubMedGoogle Scholar
  16. Hay RT (2005) SUMO: a history of modification. Mol Cell 18: 1–12.CrossRefPubMedGoogle Scholar
  17. Horn PJ, Bastie JN, Peterson CL (2005) A Rik1-associated, cullin-dependent E3 ubiquitin ligase is essential for heterochromatin formation. Genes Dev 19: 1705–1714.CrossRefPubMedGoogle Scholar
  18. Jia S, Noma K, Grewal SI (2004a) RNAi-independent heterochromatin nucleation by the stress-activated ATF/CREB family proteins. Science 304: 1971–1976.CrossRefPubMedGoogle Scholar
  19. Jia S, Yamada T, Grewal SI (2004b) Heterochromatin regulates cell type-specific long-range chromatin interactions essential for directed recombination. Cell 119: 469–480.CrossRefPubMedGoogle Scholar
  20. Jia S, Kobayashi R, Grewal SI (2005) Ubiquitin ligase component Cul4 associates with Clr4 histone methyltransferase to assemble heterochromatin. Nat Cell Biol 7: 1007–1013.CrossRefPubMedGoogle Scholar
  21. Johnson K, Shapiro-Shelef M, Tunyaplin C, Calame K (2005) Regulatory events in early and late B-cell differentiation. Mol Immunol 42: 749–761.CrossRefPubMedGoogle Scholar
  22. Kanoh J, Sadaie M, Urano T, Ishikawa F (2005) Telomere binding protein Taz1 establishes Swi6 heterochromatin independently of RNAi at telomeres. Curr Biol 15: 1808–1819.CrossRefPubMedGoogle Scholar
  23. Kato H, Goto DB, Martienssen RA, Urano T, Furukawa K, Murakami Y (2005) RNA polymerase II is required for RNAi-dependent heterochromatin assembly. Science 309: 467–469.CrossRefPubMedGoogle Scholar
  24. Kim HS, Choi ES, Shin JA, Jang YK, Park SD (2004) Regulation of Swi6/HP1-dependent heterochromatin assembly by cooperation of components of the mitogen-activated protein kinase pathway and a histone deacetylase Clr6. J Biol Chem 279: 42850–42859.PubMedGoogle Scholar
  25. Kniola B, O'Toole E, McIntosh JR et al. (2001) The domain structure of centromeres is conserved from fission yeast to humans. Mol Biol Cell 12: 2767–2775.PubMedGoogle Scholar
  26. Li F, Goto DB, Zaratiegui M, Tang X, Martienssen R, Cande WZ (2005) Two novel proteins, dos1 and dos2, interact with rik1 to regulate heterochromatic RNA interference and histone modification. Curr Biol 15: 1448–1457.PubMedGoogle Scholar
  27. Liu Y, Mochizuki K, Gorovsky MA (2004) Histone H3 lysine 9 methylation is required for DNA elimination in developing macronuclei in Tetrahymena. Proc Natl Acad Sci USA 101: 1679–1684.PubMedGoogle Scholar
  28. Motamedi MR, Verdel A, Colmenares SU, Gerber SA, Gygi SP, Moazed D (2004) Two RNAi complexes, RITS and RDRC, physically interact and localize to noncoding centromeric RNAs. Cell 119: 789–802.CrossRefPubMedGoogle Scholar
  29. Muratani M, Kung C, Shokat KM, Tansey WP (2005) The F box protein Dsg1/Mdm30 is a transcriptional coactivator that stimulates Gal4 turnover and cotranscriptional mRNA processing. Cell 120: 887–899.CrossRefPubMedGoogle Scholar
  30. Nakayama J, Klar AJ, Grewal SI (2000) A chromodomain protein, Swi6, performs imprinting functions in fission yeast during mitosis and meiosis. Cell 101: 307–317.CrossRefPubMedGoogle Scholar
  31. Nakayama J, Rice JC, Strahl BD, Allis CD, Grewal SI (2001) Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science 292: 110–113.CrossRefPubMedGoogle Scholar
  32. Neuwald AF, Poleksic A (2000) PSI-BLAST searches using hidden markov models of structural repeats: prediction of an unusual sliding DNA clamp and of beta-propellers in UV-damaged DNA-binding protein. Nucleic Acids Res 28: 3570–3580.CrossRefPubMedGoogle Scholar
  33. Nimmo ER, Cranston G, Allshire RC (1994) Telomere-associated chromosome breakage in fission yeast results in variegated expression of adjacent genes. EMBO J 13: 3801–3811.PubMedGoogle Scholar
  34. Noma K, Allis CD, Grewal SI (2001) Transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries. Science 293: 1150–1155.CrossRefPubMedGoogle Scholar
  35. Noma K, Sugiyama T, Cam H et al. (2004) RITS acts in cis to promote RNA interference-mediated transcriptional and post-transcriptional silencing. Nat Genet 36: 1174–1180.CrossRefPubMedGoogle Scholar
  36. Nonaka N, Kitajima T, Yokobayashi S et al. (2002) Recruitment of cohesin to heterochromatic regions by Swi6/HP1 in fission yeast. Nat Cell Biol 4: 89–93.CrossRefPubMedGoogle Scholar
  37. Obuse C, Yang H, Nozaki N, Goto S, Okazaki T, Yoda K (2004) Proteomics analysis of the centromere complex from HeLa interphase cells: UV-damaged DNA binding protein 1 (DDB-1) is a component of the CEN-complex, while BMI-1 is transiently co-localized with the centromeric region in interphase. Genes Cells 9: 105–120.CrossRefPubMedGoogle Scholar
  38. Osaka F, Saeki M, Katayama S et al. (2000) Covalent modifier NEDD8 is essential for SCF ubiquitin-ligase in fission yeast. EMBO J 19: 3475–3484.CrossRefPubMedGoogle Scholar
  39. Partridge JF, Borgstrom B, Allshire RC (2000) Distinct protein interaction domains and protein spreading in a complex centromere. Genes Dev 14 783–791.PubMedGoogle Scholar
  40. Partridge JF, Scott KS, Bannister AJ, Kouzarides T, Allshire RC (2002) Cis-acting DNA from fission yeast centromeres mediates histone H3 methylation and recruitment of silencing factors and cohesin to an ectopic site. Curr Biol 12: 1652–1660.CrossRefPubMedGoogle Scholar
  41. Peng J, Schwartz D, Elias JE et al. (2003) A proteomics approach to understanding protein ubiquitination. Nat Biotechnol 21: 921–926.CrossRefPubMedGoogle Scholar
  42. Petrie VJ, Wuitschick JD, Givens CD, Kosinski AM, Partridge JF (2005) RNA interference (RNAi)-dependent and RNAi-independent association of the Chp1 chromodomain protein with distinct heterochromatic loci in fission yeast. Mol Cell Biol 25: 2331–2346.CrossRefPubMedGoogle Scholar
  43. Petroski MD, Deshaies RJ (2005) Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol 6: 9–20.CrossRefPubMedGoogle Scholar
  44. Pickart CM (2001) Mechanisms underlying ubiquitination. Annu Rev Biochem 70: 503–533.CrossRefPubMedGoogle Scholar
  45. Reinhart BJ, Bartel DP (2002) Small RNAs correspond to centromere heterochromatic repeats. Science 297: 1831.CrossRefPubMedGoogle Scholar
  46. Rogakou EP, Boon C, Redon C, Bonner WM (1999) Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol 146: 905–916.CrossRefPubMedGoogle Scholar
  47. Roguev A, Schaft D, Shevchenko A, Aasland R, Shevchenko A, Stewart AF (2003) High conservation of the Set1/Rad6 axis of histone 3 lysine 4 methylation in budding and fission yeasts. J Biol Chem 278: 8487–8493.CrossRefPubMedGoogle Scholar
  48. Sadaie M, Iida T, Urano T, Nakayama J (2004) A chromodomain protein, Chp1, is required for the establishment of heterochromatin in fission yeast. EMBO J 23: 3825–3835.CrossRefPubMedGoogle Scholar
  49. Schramke V, Sheedy DM, Denli AM et al. (2005) RNA-interference-directed chromatin modification coupled to RNA polymerase II transcription. Nature 435: 1275–1279.CrossRefPubMedGoogle Scholar
  50. Shankaranarayana GD, Motamedi MR, Moazed D, Grewal SI (2003) Sir2 regulates histone H3 lysine 9 methylation and heterochromatin assembly in fission yeast. Curr Biol 13: 1240–1246.CrossRefPubMedGoogle Scholar
  51. Shin JA, Choi ES, Kim HS et al. (2005) SUMO modification is involved in the maintenance of heterochromatin stability in fission yeast. Mol Cell 19: 817–828.CrossRefPubMedGoogle Scholar
  52. Sigova A, Rhind N, Zamore PD (2004) A single Argonaute protein mediates both transcriptional and posttranscriptional silencing in Schizosaccharomyces pombe. Genes Dev 18: 2359–2367.CrossRefPubMedGoogle Scholar
  53. Sullivan BA, Karpen GH (2004) Centromeric chromatin exhibits a histone modification pattern that is distinct from both euchromatin and heterochromatin. Nat Struct Mol Biol 11: 1076–1083.CrossRefPubMedGoogle Scholar
  54. Sun L, Chen ZJ (2004) The novel functions of ubiquitination in signaling. Curr Opin Cell Biol 16: 119–126.PubMedGoogle Scholar
  55. Sun ZW, Allis CD (2002) Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature 418: 104–108.PubMedGoogle Scholar
  56. Thon G, Verhein-Hansen J (2000) Four chromo-domain proteins of Schizosaccharomyces pombe differentially repress transcription at various chromosomal locations. Genetics 155: 551–568.PubMedGoogle Scholar
  57. Thon G, Cohen A, Klar AJ (1994) Three additional linkage groups that repress transcription and meiotic recombination in the mating-type region of Schizosaccharomyces pombe. Genetics 138: 29–38.PubMedGoogle Scholar
  58. Thon G, Hansen KR, Altes SP et al. (2005) The Clr7 and Clr8 directionality factors and the Pcu4 cullin mediate heterochromatin formation in the fission yeast Schizosaccharomyces pombe. Genetics 171: 1583–1595.Google Scholar
  59. Tuzon CT, Borgstrom B, Weilguny D, Egel R, Cooper JP, Nielsen O (2004) The fission yeast heterochromatin protein Rik1 is required for telomere clustering during meiosis. J Cell Biol 165: 759–765.CrossRefPubMedGoogle Scholar
  60. Vakoc CR, Mandat SA, Olenchock BA, Blobel GA (2005) Histone H3 lysine 9 methylation and HP1gamma are associated with transcription elongation through mammalian chromatin. Mol Cell 19: 381–391.CrossRefPubMedGoogle Scholar
  61. Verdel A, Moazed D (2005) RNAi-directed assembly of heterochromatin in fission yeast. FEBS Lett 579: 5872–5878.CrossRefPubMedGoogle Scholar
  62. Verdel A, Jia S, Gerber S et al. (2004) RNAi-mediated targeting of heterochromatin by the RITS complex. Science 303: 672–676.CrossRefPubMedGoogle Scholar
  63. Volpe TA, Kidner C, Hall IM, Teng G, Grewal SI, Martienssen RA (2002) Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 297: 1833–1837.CrossRefPubMedGoogle Scholar
  64. Volpe T, Schramke V, Hamilton GL et al. (2003) RNA interference is required for normal centromere function in fission yeast. Chromosome Res 11: 137–146.CrossRefPubMedGoogle Scholar
  65. Wood A, Krogan NJ, Dover J et al. (2003) Bre1, an E3 ubiquitin ligase required for recruitment and substrate selection of Rad6 at a promoter. Mol Cell 11: 267–274.CrossRefPubMedGoogle Scholar
  66. Wysocka J, Swigut T, Milne TA et al. (2005) WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell 121: 859–872.CrossRefPubMedGoogle Scholar
  67. Xhemalce B, Seeler JS, Thon G, Dejean A, Arcangioli B (2004) Role of the fission yeast SUMO E3 ligase Pli1p in centromere and telomere maintenance. EMBO J 23: 3844–3853.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  1. 1.Program in Molecular MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA

Personalised recommendations