Nothing Special   »   [go: up one dir, main page]

Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Transcription and RNA interference in the formation of heterochromatin

Abstract

Transcription in heterochromatin seems to be an oxymoron — surely the 'silenced' form of chromatin should not be transcribed. But there have been frequent reports of low-level transcription in heterochromatic regions, and several hundred genes are found in these regions in Drosophila. Most strikingly, recent investigations implicate RNA interference mechanisms in targeting and maintaining heterochromatin, and these mechanisms are inherently dependent on transcription. Silencing of chromatin might involve trans-acting sources of the crucial small RNAs that carry out RNA interference, but in some cases, transcription of the region to be silenced seems to be required — an apparent contradiction.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Changes in histone modification implicated in the switch from a euchromatic to a heterochromatic state in Drosophila.
Figure 2: Variegating phenotypes.
Figure 3: HP1 and its interactions.
Figure 4: Model showing RNAi-mediated heterochromatin assembly and silencing in S. pombe.

Similar content being viewed by others

References

  1. Grewal, S. I. & Elgin, S. C. Heterochromatin: new possibilities for the inheritance of structure. Curr. Opin. Genet. Dev. 12, 178–187 (2002).

    CAS  PubMed  Google Scholar 

  2. Sun, F. L., Cuaycong, M. H. & Elgin, S. C. Long-range nucleosome ordering is associated with gene silencing in Drosophila melanogaster pericentric heterochromatin. Mol. Cell. Biol. 21, 2867–2879 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Sugiyama, T. et al. SHREC, an effector complex for heterochromatic transcriptional silencing. Cell 128, 491–504 (2007).

    CAS  PubMed  Google Scholar 

  4. Wallrath, L. L. & Elgin, S. C. Position effect variegation in Drosophila is associated with an altered chromatin structure. Genes Dev. 9, 1263–1277 (1995).

    CAS  PubMed  Google Scholar 

  5. Cryderman, D. E., Tang, H., Bell, C., Gilmour, D. S. & Wallrath, L. L. Heterochromatic silencing of Drosophila heat shock genes acts at the level of promoter potentiation. Nucleic Acids Res. 27, 3364–3370 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Yamada, T., Fischle, W., Sugiyama, T., Allis, C. D. & Grewal, S. I. The nucleation and maintenance of heterochromatin by a histone deacetylase in fission yeast. Mol. Cell 20, 173–185 (2005).

    CAS  PubMed  Google Scholar 

  7. Hall, I. M. et al. Establishment and maintenance of a heterochromatin domain. Science 297, 2232–2237 (2002).

    ADS  CAS  PubMed  Google Scholar 

  8. Ahmad, K. & Henikoff, S. Modulation of a transcription factor counteracts heterochromatic gene silencing in Drosophila. Cell 104, 839–847 (2001).

    CAS  PubMed  Google Scholar 

  9. Yasuhara, J. C. & Wakimoto, B. T. Oxymoron no more: the expanding world of heterochromatic genes. Trends Genet. 22, 330–338 (2006).

    CAS  PubMed  Google Scholar 

  10. Elgin, S. C. R. & Reuter, G. in Epigenetics (eds Allis, C. D., Jenuwein, T. & Reinberg, R.) 81–100 (Cold Spring Harbor Laboratory Press, Woodbury, 2007).

    Google Scholar 

  11. Schotta, G. et al. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev. 18, 1251–1262 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Locke, J., Kotarski, M. A. & Tartof, K. D. Dosage-dependent modifiers of position effect variegation in Drosophila and a mass action model that explains their effect. Genetics 120, 181–198 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Eissenberg, J. C. et al. Mutation in a heterochromatin-specific chromosomal protein is associated with suppression of position-effect variegation in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 87, 9923–9927 (1990).

    ADS  CAS  PubMed  Google Scholar 

  14. Shaffer, C. D. et al. Heterochromatin protein 2 (HP2), a partner of HP1 in Drosophila heterochromatin. Proc. Natl Acad. Sci. USA 99, 14332–14337 (2002).

    ADS  CAS  PubMed  Google Scholar 

  15. Reuter, G. et al. Dependence of position-effect variegation in Drosophila on dose of a gene encoding an unusual zinc-finger protein. Nature 344, 219–223 (1990).

    ADS  CAS  PubMed  Google Scholar 

  16. Tschiersch, B. et al. The protein encoded by the Drosophila position-effect variegation suppressor gene Su(var)3-9 combines domains of antagonistic regulators of homeotic gene complexes. Embo J. 13, 3822–3831 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Greil, F., de Wit, E., Bussemaker, H. J. & van Steensel, B. HP1 controls genomic targeting of four novel heterochromatin proteins in Drosophila. Embo J. 26, 741–751 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Talbert, P. B. & Henikoff, S. Spreading of silent chromatin: inaction at a distance. Nature Rev. Genet. 7, 793–803 (2006).

    CAS  PubMed  Google Scholar 

  19. Huisinga, K. L., Brower-Toland, B. & Elgin, S. C. The contradictory definitions of heterochromatin: transcription and silencing. Chromosoma 115, 110–122 (2006).

    CAS  PubMed  Google Scholar 

  20. Grewal, S. I. & Jia, S. Heterochromatin revisited. Nature Rev. Genet. 8, 35–46 (2007).

    CAS  PubMed  Google Scholar 

  21. Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).

    ADS  CAS  PubMed  Google Scholar 

  22. Nakayama, J., Rice, J. C., Strahl, B. D., Allis, C. D. & Grewal, S. I. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science 292, 110–113 (2001).

    ADS  CAS  PubMed  Google Scholar 

  23. Jia, S., Kobayashi, R. & Grewal, S. I. Ubiquitin ligase component Cul4 associates with Clr4 histone methyltransferase to assemble heterochromatin. Nature Cell Biol. 7, 1007–1013 (2005).

    CAS  PubMed  Google Scholar 

  24. Hong, E. J. E., Villen, J., Gerace, E. L., Gygi, S. & Moazed, D. A cullin E3 ubiquitin ligase complex associates with Rik1 and the Clr4 histone H3-K9 methyltransferase and is required for RNAi-mediated heterochromatin formation. RNA Biol. 2, 106–111 (2005).

    CAS  PubMed  Google Scholar 

  25. Horn, P. J., Bastie, J. N. & Peterson, C. L. A Rik1-associated, cullin-dependent E3 ubiquitin ligase is essential for heterochromatin formation. Genes Dev. 19, 1705–1714 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Thon, G. et al. The Clr7 and Clr8 directionality factors and the Pcu4 cullin mediate heterochromatin formation in the fission yeast Schizosaccharomyces pombe. Genetics 171, 1583–1595 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001).

    ADS  CAS  PubMed  Google Scholar 

  28. Partridge, J. F., Scott, K. S., Bannister, A. J., Kouzarides, T. & Allshire, R. C. 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 (2002).

    CAS  PubMed  Google Scholar 

  29. Sadaie, M., Iida, T., Urano, T. & Nakayama, J. A chromodomain protein, Chp1, is required for the establishment of heterochromatin in fission yeast. Embo J. 23, 3825–3835 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Cam, H. P. et al. Comprehensive analysis of heterochromatin- and RNAi-mediated epigenetic control of the fission yeast genome. Nature Genet. 37, 809–819 (2005).

    CAS  PubMed  Google Scholar 

  31. Grewal, S. I. & Klar, A. J. A recombinationally repressed region between mat2 and mat3 loci shares homology to centromeric repeats and regulates directionality of mating-type switching in fission yeast. Genetics 146, 1221–1238 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kanoh, J., Sadaie, M., Urano, T. & Ishikawa, F. Telomere binding protein Taz1 establishes Swi6 heterochromatin independently of RNAi at telomeres. Curr. Biol. 15, 1808–1819 (2005).

    CAS  PubMed  Google Scholar 

  33. Volpe, T. A. et al. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 297, 1833–1837 (2002).

    ADS  CAS  PubMed  Google Scholar 

  34. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).

    ADS  CAS  PubMed  Google Scholar 

  35. Verdel, A. et al. RNAi-mediated targeting of heterochromatin by the RITS complex. Science 303, 672–676 (2004).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  36. Noma, K. et al. RITS acts in cis to promote RNA interference-mediated transcriptional and post-transcriptional silencing. Nature Genet. 36, 1174–1180 (2004).

    CAS  PubMed  Google Scholar 

  37. Sugiyama, T., Cam, H., Verdel, A., Moazed, D. & Grewal, S. I. RNA-dependent RNA polymerase is an essential component of a self-enforcing loop coupling heterochromatin assembly to siRNA production. Proc. Natl Acad. Sci. USA 102, 152–157 (2005).

    ADS  CAS  PubMed  Google Scholar 

  38. Motamedi, M. R. et al. Two RNAi complexes, RITS and RDRC, physically interact and localize to noncoding centromeric RNAs. Cell 119, 789–802 (2004).

    CAS  PubMed  Google Scholar 

  39. Irvine, D. V. et al. Argonaute slicing is required for heterochromatic silencing and spreading. Science 313, 1134–1137 (2006).

    ADS  CAS  PubMed  Google Scholar 

  40. Zofall, M. & Grewal, S. I. RNAi-mediated heterochromatin assembly in fission yeast. Cold Spring Harb. Symp. Quant. Biol. 71, 487–496 (2006).

    CAS  PubMed  Google Scholar 

  41. Grewal, S. I. & Moazed, D. Heterochromatin and epigenetic control of gene expression. Science 301, 798–802 (2003).

    ADS  CAS  Google Scholar 

  42. Buhler, M., Verdel, A. & Moazed, D. Tethering RITS to a nascent transcript initiates RNAi- and heterochromatin-dependent gene silencing. Cell 125, 873–886 (2006).

    CAS  PubMed  Google Scholar 

  43. Djupedal, I. et al. RNA Pol II subunit Rpb7 promotes centromeric transcription and RNAi-directed chromatin silencing. Genes Dev. 19, 2301–2306 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kato, H. et al. RNA polymerase II is required for RNAi-dependent heterochromatin assembly. Science 309, 467–469 (2005).

    ADS  CAS  PubMed  Google Scholar 

  45. Ayoub, N. et al. A novel jmjC domain protein modulates heterochromatization in fission yeast. Mol. Cell. Biol. 23, 4356–4370 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Klose, R. J., Kallin, E. M. & Zhang, Y. JmjC-domain-containing proteins and histone demethylation. Nature Rev. Genet. 7, 715–727 (2006).

    CAS  PubMed  Google Scholar 

  47. Tsukada, Y. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006).

    ADS  CAS  PubMed  Google Scholar 

  48. Mochizuki, K. & Gorovsky, M. A. Small RNAs in genome rearrangement in Tetrahymena. Curr. Opin. Genet. Dev. 14, 181–187 (2004).

    CAS  PubMed  Google Scholar 

  49. Vagin, V. V. et al. A distinct small RNA pathway silences selfish genetic elements in the germline. Science 313, 320–324 (2006).

    ADS  CAS  PubMed  Google Scholar 

  50. Richards, E. J. & Elgin, S. C. Epigenetic codes for heterochromatin formation and silencing: rounding up the usual suspects. Cell 108, 489–500 (2002).

    CAS  PubMed  Google Scholar 

  51. Pal-Bhadra, M., Bhadra, U. & Birchler, J. A. RNAi related mechanisms affect both transcriptional and posttranscriptional transgene silencing in Drosophila. Mol. Cell 9, 315–327 (2002).

    CAS  PubMed  Google Scholar 

  52. Pal-Bhadra, M. et al. Heterochromatic silencing and HP1 localization in Drosophila are dependent on the RNAi machinery. Science 303, 669–672 (2004).

    ADS  CAS  PubMed  Google Scholar 

  53. Haynes, K. A., Caudy, A. A., Collins, L. & Elgin, S. C. Element 1360 and RNAi components contribute to HP1-dependent silencing of a pericentric reporter. Curr. Biol. 16, 2222–2227 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. van Rij, R. P. et al. The RNA silencing endonuclease Argonaute 2 mediates specific antiviral immunity in Drosophila melanogaster. Genes Dev. 20, 2985–2995 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang, X. H. et al. RNA interference directs innate immunity against viruses in adult Drosophila. Science 312, 452–454 (2006).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kalmykova, A. I., Klenov, M. S. & Gvozdev, V. A. Argonaute protein PIWI controls mobilization of retrotransposons in the Drosophila male germline. Nucleic Acids Res. 33, 2052–2059 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Saito, K. et al. Specific association of Piwi with rasiRNAs derived from retrotransposon and heterochromatic regions in the Drosophila genome. Genes Dev. 20, 2214–2222 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Deshpande, G., Calhoun, G. & Schedl, P. Drosophila argonaute-2 is required early in embryogenesis for the assembly of centric/centromeric heterochromatin, nuclear division, nuclear migration, and germ-cell formation. Genes Dev. 19, 1680–1685 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Allshire, R. C., Nimmo, E. R., Ekwall, K., Javerzat, J. P. & Cranston, G. Mutations derepressing silent centromeric domains in fission yeast disrupt chromosome segregation. Genes Dev. 9, 218–233 (1995).

    CAS  PubMed  Google Scholar 

  60. Fukagawa, T. et al. Dicer is essential for formation of the heterochromatin structure in vertebrate cells. Nature Cell Biol. 6, 784–791 (2004).

    CAS  PubMed  Google Scholar 

  61. Hall, I. M., Noma, K. & Grewal, S. I. RNA interference machinery regulates chromosome dynamics during mitosis and meiosis in fission yeast. Proc. Natl Acad. Sc.i USA 100, 193–198 (2003).

    ADS  CAS  Google Scholar 

  62. Peng, J. C. & Karpen, G. H. H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability. Nature Cell Biol. 9, 25–35 (2007).

    CAS  PubMed  Google Scholar 

  63. Jia, S., Noma, K. & Grewal, S. I. RNAi-independent heterochromatin nucleation by the stress-activated ATF/CREB family proteins. Science 304, 1971–1976 (2004).

    ADS  CAS  PubMed  Google Scholar 

  64. Kim, H. S., Choi, E. S., Shin, J. A., Jang, Y. K. & Park, S. D. 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 (2004).

    CAS  PubMed  Google Scholar 

  65. Schultz, D., Ayyanathan, K., Negorev, D., Maul, G. & Rauscher, F. R. SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev. 16, 1855–1869 (2002).

    Google Scholar 

  66. Aulner, N. et al. The AT-hook protein D1 is essential for Drosophila melanogaster development and is implicated in position-effect variegation. Mol. Cell. Biol. 22, 1218–1232 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Blattes, R. et al. Displacement of D1, HP1 and topoisomerase II from satellite heterochromatin by a specific polyamide. Embo J. 25, 2397–2408 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Huertas, D., Cortes, A., Casanova, J. & Azorin, F. Drosophila DDP1, a multi-KH-domain protein, contributes to centromeric silencing and chromosome segregation. Curr. Biol. 14, 1611–1620 (2004).

    CAS  PubMed  Google Scholar 

  69. Sun, F. L. et al. cis-Acting determinants of heterochromatin formation on Drosophila melanogaster chromosome four. Mol. Cell. Biol. 24, 8210–8220 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Aravin, A. A. et al. The small RNA profile during Drosophila melanogaster development. Dev. Cell 5, 337–350 (2003).

    CAS  PubMed  Google Scholar 

  71. Aravin, A. A. et al. Double-stranded RNA-mediated silencing of genomic tandem repeats and transposable elements in the D. melanogaster germline. Curr. Biol. 11, 1017–1027 (2001).

    CAS  PubMed  Google Scholar 

  72. Cheutin, T. et al. Maintenance of stable heterochromatin domains by dynamic HP1 binding. Science 299, 721–725 (2003).

    ADS  CAS  PubMed  Google Scholar 

  73. Festenstein, R. et al. Modulation of heterochromatin protein 1 dynamics in primary mammalian cells. Science 299, 719–721 (2003).

    ADS  CAS  PubMed  Google Scholar 

  74. Nakayama, J., Klar, A. J. & Grewal, S. I. A chromodomain protein, Swi6, performs imprinting functions in fission yeast during mitosis and meiosis. Cell 101, 307–317 (2000).

    CAS  PubMed  Google Scholar 

  75. Grishok, A., Sinskey, J. L. & Sharp, P. A. Transcriptional silencing of a transgene by RNAi in the soma of C. elegans. Genes Dev. 19, 683–696 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Robert, V. J., Sijen, T., van Wolfswinkel, J. & Plasterk, R. H. Chromatin and RNAi factors protect the C. elegans germline against repetitive sequences. Genes Dev. 19, 782–787 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Vastenhouw, N. L. et al. Gene expression: long-term gene silencing by RNAi. Nature 442, 882 (2006).

    ADS  CAS  PubMed  Google Scholar 

  78. Sullivan, B. A. & Karpen, G. H. Centromeric chromatin exhibits a histone modification pattern that is distinct from both euchromatin and heterochromatin. Nature Struct. Mol. Biol. 11, 1076–1083 (2004).

    CAS  Google Scholar 

  79. George, J. A. & Pardue, M. L. The promoter of the heterochromatic Drosophila telomeric retrotransposon, HeT-A, is active when moved into euchromatic locations. Genetics 163, 625–635 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128, 1089–1103 (2007).

    CAS  PubMed  Google Scholar 

  81. Gunawardane, L.S. et al. A slicer-mediated mechanism for repeat-associated siRNA 5′ end formation in Drosophila. Science 315, 1587–1590 (2007).

    ADS  CAS  PubMed  Google Scholar 

  82. Rudolph, T. et al. Heterochromatin formation in Drosophila is initiated through active removal of H3K4 methylation by the LSD1 homolog SU(VAR)3-3. Mol. Cell 26, 103–115 (2007).

    CAS  PubMed  Google Scholar 

  83. Zofall, M. & Grewal, S. I. HULC, a histone H2B ubiquitinating complex, modulates heterochromatin independent of histone methylation in fission yeast. J. Biol. Chem. 282, 14065–14072 (2007).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Reprints and permissions information is available at http://npg.nature.com/reprintsandpermissions.

Correspondence should be addressed to the author (selgin@biology.wustl.edu) or S.I.S.G. (grewals@mail.nih.gov).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grewal, S., Elgin, S. Transcription and RNA interference in the formation of heterochromatin. Nature 447, 399–406 (2007). https://doi.org/10.1038/nature05914

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05914

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing