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Epigenetic regulation of centromeric chromatin: old dogs, new tricks?

Key Points

  • Chromosomal DNA is packaged with histones into nucleosomes. Following replication, sister-chromatid segregation is orchestrated to ensure that each daughter cell receives a complete set of chromosomes.

  • The centromere is the chromosomal region responsible for formation of the kinetochore, which mediates attachment to spindle microtubules and chromosome movement.

  • In organisms with complex centromeres the site of kinetochore assembly is epigenetically determined and is not strictly governed by primary DNA sequence.

  • The key determining factor in specifying the site of kinetochore assembly is the deposition of the centromere-specific histone H3 variant CENP-A.

  • In tissue-culture cells, new CENP-A is deposited during late mitosis and through G1, independently of DNA replication.

  • A portion of the histone fold domain of CENP-A is necessary and sufficient for targeting to centromeres.

  • CENP-A nucleosomes depleted during S phase replication are restored later in the cell cycle by de novo deposition into 'gaps' or by replacement of H3 nucleosomes.

  • Numerous factors have been identified that are required for CENP-A localization, but the chromatin assembly proteins that are directly required for propagation of CENP-A chromatin are not known.

  • Non-coding transcripts and transcription factors are associated with centromeres, and transcription might be linked to CENP-A chromatin assembly in some systems.

  • CENP-B binding sites and flanking centric heterochromatin influence the establishment of CENP-A chromatin on naive templates.

Abstract

The assembly of just a single kinetochore at the centromere of each sister chromatid is essential for accurate chromosome segregation during cell division. Surprisingly, despite their vital function, centromeres show considerable plasticity with respect to their chromosomal locations and activity. The establishment and maintenance of centromeric chromatin, and therefore the location of kinetochores, is epigenetically regulated. The histone H3 variant CENP-A is the key determinant of centromere identity and kinetochore assembly. Recent studies have identified many factors that affect CENP-A localization, but their precise roles in this process are unknown. We build on these advances and on new information about the timing of CENP-A assembly during the cell cycle to propose new models for how centromeric chromatin is established and propagated.

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Figure 1: Centromere structure and organization.
Figure 2: CENP-A structure and nucleosome composition.
Figure 3: Cell-cycle regulation of CENP-A assembly.
Figure 4: Nucleosome and centromere assembly pathways.
Figure 5: Possible roles for transcription of centromeric repeats.
Figure 6: Models for regulation of CENP-A propagation during the cell cycle.

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References

  1. Weaver, B. A. & Cleveland, D. W. Aneuploidy: instigator and inhibitor of tumorigenesis. Cancer Res. 67, 10103–10105 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Hassold, T. & Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nature Rev. Genet. 2, 280–291 (2001).

    CAS  PubMed  Google Scholar 

  3. Monaco, Z. L. & Moralli, D. Progress in artificial chromosome technology. Biochem. Soc. Trans. 34, 324–327 (2006).

    CAS  PubMed  Google Scholar 

  4. Westermann, S., Drubin, D. G. & Barnes, G. Structures and functions of yeast kinetochore complexes. Annu. Rev. Biochem. 76, 563–591 (2007).

    CAS  PubMed  Google Scholar 

  5. Spence, J. M. et al. Co-localization of centromere activity, proteins and topoisomerase II within a subdomain of the major human X alpha-satellite array. EMBO J. 21, 5269–5280 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Mitchell, A. R., Jeppesen, P., Nicol, L., Morrison, H. & Kipling, D. Epigenetic control of mammalian centromere protein binding: does DNA methylation have a role? J. Cell Sci. 109, 2199–2206 (1996).

    CAS  PubMed  Google Scholar 

  7. Blower, M. D., Sullivan, B. A. & Karpen, G. H. Conserved organization of centromeric chromatin in flies and humans. Dev. Cell 2, 319–330 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Lam, A. L., Boivin, C. D., Bonney, C. F., Rudd, M. K. & Sullivan, B. A. Human centromeric chromatin is a dynamic chromosomal domain that can spread over noncentromeric DNA. Proc. Natl Acad. Sci. USA 103, 4186–4191 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Henikoff, S. & Dalal, Y. Centromeric chromatin: what makes it unique? Curr. Opin. Genet. Dev. 15, 177–184 (2005).

    CAS  PubMed  Google Scholar 

  10. Dawe, R. K. & Henikoff, S. Centromeres put epigenetics in the driver's seat. Trends Biochem. Sci. 31, 662–669 (2006).

    CAS  PubMed  Google Scholar 

  11. Sullivan, B. A., Blower, M. D. & Karpen, G. H. Determining centromere identity: cyclical stories and forking paths. Nature Rev. Genet. 2, 584–596 (2001).

    CAS  PubMed  Google Scholar 

  12. Mellone, B. G. & Allshire, R. C. Stretching it: putting the CEN(P-A) in centromere. Curr. Opin. Genet. Dev. 13, 191–198 (2003).

    CAS  PubMed  Google Scholar 

  13. Karpen, G. H. & Allshire, R. C. The case for epigenetic effects on centromere identity and function. Trends Genet. 13, 489–496 (1997).

    CAS  PubMed  Google Scholar 

  14. Earnshaw, W. C. & Migeon, B. R. Three related centromere proteins are absent from the inactive centromere of a stable isodicentric chromosome. Chromosoma 92, 290–296 (1985).

    CAS  PubMed  Google Scholar 

  15. Warburton, P. E. et al. Immunolocalization of CENP-A suggests a distinct nucleosome structure at the inner kinetochore plate of active centromeres. Curr. Biol. 7, 901–904 (1997).

    CAS  PubMed  Google Scholar 

  16. Sullivan, B. A. & Schwartz, S. Identification of centromeric antigens in dicentric Robertsonian translocations: CENP-C and CENP-E are necessary components of functional centromeres. Hum. Mol. Genet. 4, 2189–2197 (1995).

    CAS  PubMed  Google Scholar 

  17. Sullivan, B. A. & Willard, H. F. Stable dicentric X chromosomes with two functional centromeres. Nature Genet. 20, 227–228 (1998).

    CAS  PubMed  Google Scholar 

  18. Agudo, M. et al. A dicentric chromosome of Drosophila melanogaster showing alternate centromere inactivation. Chromosoma 109, 190–196 (2000).

    CAS  PubMed  Google Scholar 

  19. Alonso, A. et al. Co-localization of CENP-C and CENP-H to discontinuous domains of CENP-A chromatin at human neocentromeres. Genome Biol. 8, R148 (2007).

    PubMed Central  PubMed  Google Scholar 

  20. Warburton, P. E. Chromosomal dynamics of human neocentromere formation. Chromosome Res. 12, 617–626 (2004).

    CAS  PubMed  Google Scholar 

  21. Choo, K. H. Domain organization at the centromere and neocentromere. Dev. Cell 1, 165–177 (2001).

    CAS  PubMed  Google Scholar 

  22. Lo, A. W. et al. A novel chromatin immunoprecipitation and array (CIA) analysis identifies a 460-kb CENP-A-binding neocentromere DNA. Genome Res. 11, 448–457 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Williams, B. C., Murphy, T. D., Goldberg, M. L. & Karpen, G. H. Neocentromere activity of structurally acentric mini-chromosomes in Drosophila. Nature Genet. 18, 30–37 (1998).

    CAS  PubMed  Google Scholar 

  24. Steiner, N. C. & Clarke, L. A novel epigenetic effect can alter centromere function in fission yeast. Cell 79, 865–874 (1994).

    CAS  PubMed  Google Scholar 

  25. Ishii, K. et al. Heterochromatin integrity affects chromosome reorganization after centromere dysfunction. Science 321, 1088–1091 (2008).

    CAS  PubMed  Google Scholar 

  26. Bulazel, K. V., Ferreri, G. C., Eldridge, M. D. & O'Neill, R. J. Species-specific shifts in centromere sequence composition are coincident with breakpoint reuse in karyotypically divergent lineages. Genome Biol. 8, R170 (2007).

    PubMed Central  PubMed  Google Scholar 

  27. Malik, H. S. & Henikoff, S. Conflict begets complexity: the evolution of centromeres. Curr. Opin. Genet. Dev. 12, 711–718 (2002).

    CAS  PubMed  Google Scholar 

  28. Murphy, T. D. & Karpen, G. H. Centromeres take flight: alpha satellite and the quest for the human centromere. Cell 93, 317–320 (1998).

    CAS  PubMed  Google Scholar 

  29. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    CAS  PubMed  Google Scholar 

  30. Li, B. et al. Preferential occupancy of histone variant H2AZ at inactive promoters influences local histone modifications and chromatin remodeling. Proc. Natl Acad. Sci. USA 102, 18385–18390 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Raisner, R. M. et al. Histone variant H2A.Z. marks the 5′ ends of both active and inactive genes in euchromatin. Cell 123, 233–248 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Meneghini, M. D., Wu, M. & Madhani, H. D. Conserved histone variant H2A.Z protects euchromatin from the ectopic spread of silent heterochromatin. Cell 112, 725–736 (2003).

    CAS  PubMed  Google Scholar 

  33. Greaves, I. K., Rangasamy, D., Ridgway, P. & Tremethick, D. J. H2A.Z contributes to the unique 3D structure of the centromere. Proc. Natl Acad. Sci. USA 104, 525–530 (2007).

    CAS  PubMed  Google Scholar 

  34. Ahmad, K. & Henikoff, S. The histone variant H3.3 marks active chromatin by replication-independent nucleosome assembly. Mol. Cell 9, 1191–1200 (2002).

    CAS  PubMed  Google Scholar 

  35. Mito, Y., Henikoff, J. G. & Henikoff, S. Genome-scale profiling of histone H3.3 replacement patterns. Nature Genet. 37, 1090–1097 (2005).

    CAS  PubMed  Google Scholar 

  36. Henikoff, S. Nucleosome destabilization in the epigenetic regulation of gene expression. Nature Rev. Genet. 9, 15–26 (2008).

    CAS  PubMed  Google Scholar 

  37. Mizuguchi, G. et al. ATP-driven exchange of histone H2AZ variant catalyzed by SWR1 chromatin remodeling complex. Science 303, 343–348 (2004).

    CAS  PubMed  Google Scholar 

  38. Tagami, H., Ray-Gallet, D., Almouzni, G. & Nakatani, Y. Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Cell 116, 51–61 (2004).

    CAS  PubMed  Google Scholar 

  39. Meluh, P. B., Yang, P., Glowczewski, L., Koshland, D. & Smith, M. M. Cse4p is a component of the core centromere of Saccharomyces cerevisiae. Cell 94, 607–613 (1998).

    CAS  PubMed  Google Scholar 

  40. Buchwitz, B. J., Ahmad, K., Moore, L. L., Roth, M. B. & Henikoff, S. A histone-H3-like protein in C. elegans. Nature 401, 547–548 (1999).

    CAS  PubMed  Google Scholar 

  41. Blower, M. D. & Karpen, G. H. The role of Drosophila CID in kinetochore formation, cell-cycle progression and heterochromatin interactions. Nature Cell Biol. 3, 730–739 (2001).

    CAS  PubMed  Google Scholar 

  42. Henikoff, S., Ahmad, K., Platero, J. S. & van Steensel, B. Heterochromatic deposition of centromeric histone H3-like proteins. Proc. Natl Acad. Sci. USA 97, 716–721 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Stoler, S., Keith, K. C., Curnick, K. E. & Fitzgerald-Hayes, M. A mutation in CSE4, an essential gene encoding a novel chromatin-associated protein in yeast, causes chromosome nondisjunction and cell cycle arrest at mitosis. Genes Dev. 9, 573–586 (1995).

    CAS  PubMed  Google Scholar 

  44. Takahashi, K., Chen, E. S. & Yanagida, M. Requirement of Mis6 centromere connector for localizing a CENP-A-like protein in fission yeast. Science 288, 2215–2219 (2000).

    CAS  PubMed  Google Scholar 

  45. Sullivan, K. F., Hechenberger, M. & Masri, K. Human CENP-A contains a histone H3 related histone fold domain that is required for targeting to the centromere. J. Cell Biol. 127, 581–592 (1994).

    CAS  PubMed  Google Scholar 

  46. Palmer, D. K., O'Day, K., Wener, M. H., Andrews, B. S. & Margolis, R. L. A 17-kD centromere protein (CENP-A) copurifies with nucleosome core particles and with histones. J. Cell Biol. 104, 805–815 (1987).

    CAS  PubMed  Google Scholar 

  47. Heun, P. et al. Mislocalization of the Drosophila centromere-specific histone CID promotes formation of functional ectopic kinetochores. Dev. Cell 10, 303–315 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Furuyama, S. & Biggins, S. Centromere identity is specified by a single centromeric nucleosome in budding yeast. Proc. Natl Acad. Sci. USA 104, 14706–14711 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Yan, H. & Jiang, J. Rice as a model for centromere and heterochromatin research. Chromosome Res. 15, 77–84 (2007).

    CAS  PubMed  Google Scholar 

  50. 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 

  51. Castillo, A. G. et al. Plasticity of fission yeast CENP-A chromatin driven by relative levels of histone H3 and H4. PLoS Genet. 3, e121 (2007).

    PubMed Central  PubMed  Google Scholar 

  52. 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 

  53. Yeh, E. et al. Pericentric chromatin is organized into an intramolecular loop in mitosis. Curr. Biol. 18, 81–90 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Gregan, J. et al. The kinetochore proteins Pcs1 and Mde4 and heterochromatin are required to prevent merotelic orientation. Curr. Biol. 17, 1190–1200 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Black, B. E. et al. Structural determinants for generating centromeric chromatin. Nature 430, 578–582 (2004).

    CAS  PubMed  Google Scholar 

  56. Polizzi, C. & Clarke, L. The chromatin structure of centromeres from fission yeast: differentiation of the central core that correlates with function. J. Cell Biol. 112, 191–201 (1991).

    CAS  PubMed  Google Scholar 

  57. Takahashi, K. et al. A low copy number central sequence with strict symmetry and unusual chromatin structure in fission yeast centromere. Mol. Biol. Cell 3, 819–835 (1992).

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Baum, M., Sanyal, K., Mishra, P. K., Thaler, N. & Carbon, J. Formation of functional centromeric chromatin is specified epigenetically in Candida albicans. Proc. Natl Acad. Sci. USA 103, 14877–14882 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Yoda, K. et al. Human centromere protein A (CENP-A) can replace histone H3 in nucleosome reconstitution in vitro. Proc. Natl Acad. Sci. USA 97, 7266–7271 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Black, B. E., Brock, M. A., Bedard, S., Woods, V. L. Jr & Cleveland, D. W. An epigenetic mark generated by the incorporation of CENP-A into centromeric nucleosomes. Proc. Natl Acad. Sci. USA 104, 5008–5013 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Conde e Silva, N. et al. CENP-A-containing nucleosomes: easier disassembly versus exclusive centromeric localization. J. Mol. Biol. 370, 555–573 (2007).

    CAS  PubMed  Google Scholar 

  62. Mizuguchi, G., Xiao, H., Wisniewski, J., Smith, M. M. & Wu, C. Nonhistone Scm3 and histones CenH3–H4 assemble the core of centromere-specific nucleosomes. Cell 129, 1153–1164 (2007).

    CAS  PubMed  Google Scholar 

  63. Dalal, Y., Wang, H., Lindsay, S. & Henikoff, S. Tetrameric structure of centromeric nucleosomes in interphase Drosophila cells. PLoS Biol. 5, e218 (2007).

    PubMed Central  PubMed  Google Scholar 

  64. Black, B. E. & Bassett, E. A. The histone variant CENP-A and centromere specification. Curr. Opin. Cell Biol. 20, 91–100 (2008).

    CAS  PubMed  Google Scholar 

  65. Foltz, D. R. et al. The human CENP-A centromeric nucleosome-associated complex. Nature Cell Biol. 8, 458–469 (2006).

    CAS  PubMed  Google Scholar 

  66. Maruyama, T., Nakamura, T., Hayashi, T. & Yanagida, M. Histone H2B mutations in inner region affect ubiquitination, centromere function, silencing and chromosome segregation. EMBO J. 25, 2420–2431 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Sogo, J. M., Stahl, H., Koller, T. & Knippers, R. Structure of replicating simian virus 40 minichromosomes. The replication fork, core histone segregation and terminal structures. J. Mol. Biol. 189, 189–204 (1986).

    CAS  PubMed  Google Scholar 

  68. Mello, J. A. & Almouzni, G. The ins and outs of nucleosome assembly. Curr. Opin. Genet. Dev. 11, 136–141 (2001).

    CAS  PubMed  Google Scholar 

  69. Rocha, W. & Verreault, A. Clothing up DNA for all seasons: histone chaperones and nucleosome assembly pathways. FEBS Lett. 582, 1938–1949 (2008).

    CAS  PubMed  Google Scholar 

  70. Sugasawa, K. et al. Nonconservative segregation of parental nucleosomes during simian virus 40 chromosome replication in vitro. Proc. Natl Acad. Sci. USA 89, 1055–1059 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Shelby, R. D., Monier, K. & Sullivan, K. F. Chromatin assembly at kinetochores is uncoupled from DNA replication. J. Cell Biol. 151, 1113–1118 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Sullivan, B. & Karpen, G. Centromere identity in Drosophila is not determined in vivo by replication timing. J. Cell Biol. 154, 683–690 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Kim, S. M., Dubey, D. D. & Huberman, J. A. Early-replicating heterochromatin. Genes Dev. 17, 330–335 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Pearson, C. G. et al. Stable kinetochore–microtubule attachment constrains centromere positioning in metaphase. Curr. Biol. 14, 1962–1967 (2004).

    CAS  PubMed  Google Scholar 

  75. Jansen, L. E., Black, B. E., Foltz, D. R. & Cleveland, D. W. Propagation of centromeric chromatin requires exit from mitosis. J. Cell Biol. 176, 795–805 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Takayama, Y. et al. Biphasic incorporation of centromeric histone CENP-A in fission yeast. Mol. Biol. Cell 19, 682–690 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Chen, E. S., Saitoh, S., Yanagida, M. & Takahashi, K. A cell cycle-regulated GATA factor promotes centromeric localization of CENP-A in fission yeast. Mol. Cell 11, 175–187 (2003).

    CAS  PubMed  Google Scholar 

  78. Takayama, Y. & Takahashi, K. Differential regulation of repeated histone genes during the fission yeast cell cycle. Nucleic Acids Res. 35, 3223–3237 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Schuh, M., Lehner, C. F. & Heidmann, S. Incorporation of Drosophila CID/CENP-A and CENP-C into centromeres during early embryonic anaphase. Curr. Biol. 17, 237–243 (2007).

    CAS  PubMed  Google Scholar 

  80. Carroll, C. W. & Straight, A. F. Centromere formation: from epigenetics to self-assembly. Trends Cell Biol. 16, 70–78 (2006).

    CAS  PubMed  Google Scholar 

  81. Keith, K. C. et al. Analysis of primary structural determinants that distinguish the centromere-specific function of histone variant Cse4p from histone H3. Mol. Cell Biol. 19, 6130–6139 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Shelby, R. D., Vafa, O. & Sullivan, K. F. Assembly of CENP-A into centromeric chromatin requires a cooperative array of nucleosomal DNA contact sites. J. Cell Biol. 136, 501–513 (1997).

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Vermaak, D., Hayden, H. S. & Henikoff, S. Centromere targeting element within the histone fold domain of Cid. Mol. Cell Biol. 22, 7553–7561 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Camahort, R. et al. Scm3 is essential to recruit the histone H3 variant Cse4 to centromeres and to maintain a functional kinetochore. Mol. Cell 26, 853–865 (2007).

    CAS  PubMed  Google Scholar 

  85. Stoler, S. et al. Scm3, an essential Saccharomyces cerevisiae centromere protein required for G2/M progression and Cse4 localization. Proc. Natl Acad. Sci. USA 104, 10571–10576 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Saitoh, S., Takahashi, K. & Yanagida, M. Mis6, a fission yeast inner centromere protein, acts during G1/S and forms specialized chromatin required for equal segregation. Cell 90, 131–143 (1997).

    CAS  PubMed  Google Scholar 

  87. Hayashi, T. et al. Mis16 and Mis18 are required for CENP-A loading and histone deacetylation at centromeres. Cell 118, 715–729 (2004).

    CAS  PubMed  Google Scholar 

  88. Maddox, P. S., Hyndman, F., Monen, J., Oegema, K. & Desai, A. Functional genomics identifies a Myb domain-containing protein family required for assembly of CENP-A chromatin. J. Cell Biol. 176, 757–763 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Fujita, Y. et al. Priming of centromere for CENP-A recruitment by human hMis18alpha, hMis18beta, and M18BP1. Dev. Cell 12, 17–30 (2007).

    CAS  PubMed  Google Scholar 

  90. Dunleavy, E. M. et al. A NASP (N1/N2)-related protein, Sim3, binds CENP-A and is required for its deposition at fission yeast centromeres. Mol. Cell 28, 1029–1044 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Okada, M. et al. The CENP-H-I complex is required for the efficient incorporation of newly synthesized CENP-A into centromeres. Nature Cell Biol. 8, 446–457 (2006).

    CAS  PubMed  Google Scholar 

  92. Erhardt, S., Mellone, B. G., Betts, C. M., Zhang, W., Karpen G. H. & Straight, A. F. Genome-wide analysis reveals a cell-cycle-dependent mechanism controlling centromere propagation. J. Cell Biol. (in the press).

  93. Ahmad, K. & Henikoff, S. Centromeres are specialized replication domains in heterochromatin. J. Cell Biol. 153, 101–110 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Furuyama, T., Dalal, Y. & Henikoff, S. Chaperone-mediated assembly of centromeric chromatin in vitro. Proc. Natl Acad. Sci. USA 103, 6172–6177 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Carlson, S. R. et al. Meiotic transmission of an in vitro-assembled autonomous maize minichromosome. PLoS Genet. 3, 1965–1974 (2007).

    CAS  PubMed  Google Scholar 

  96. Harrington, J. J., Van Bokkelen, G., Mays, R. W., Gustashaw, K. & Willard, H. F. Formation of de novo centromeres and construction of first-generation human artificial microchromosomes. Nature Genet. 15, 345–355 (1997).

    CAS  PubMed  Google Scholar 

  97. Ikeno, M. et al. Construction of YAC-based mammalian artificial chromosomes. Nature Biotechnol. 16, 431–439 (1998).

    CAS  Google Scholar 

  98. Hahnenberger, K. M., Baum, M. P., Polizzi, C. M., Carbon, J. & Clarke, L. Construction of functional artificial minichromosomes in the fission yeast Schizosaccharomyces pombe. Proc. Natl Acad. Sci. USA 86, 577–581 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Clarke, L. & Carbon, J. Isolation of a yeast centromere and construction of functional small circular chromosomes. Nature 287, 504–509 (1980).

    CAS  PubMed  Google Scholar 

  100. Okada, T. et al. CENP-B controls centromere formation depending on the chromatin context. Cell 131, 1287–1300 (2007).

    CAS  PubMed  Google Scholar 

  101. Nakano, M. et al. Inactivation of a human kinetochore by specific targeting of chromatin modifiers. Dev. Cell 14, 507–522 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Folco, H. D., Pidoux, A. L., Urano, T. & Allshire, R. C. Heterochromatin and RNAi are required to establish CENP-A chromatin at centromeres. Science 319, 94–97 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Buhler, M. & Moazed, D. Transcription and RNAi in heterochromatic gene silencing. Nature Struct. Mol. Biol. 14, 1041–1048 (2007).

    Google Scholar 

  104. Grewal, S. I. & Elgin, S. C. Transcription and RNA interference in the formation of heterochromatin. Nature 447, 399–406 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Grummt, I. Different epigenetic layers engage in complex crosstalk to define the epigenetic state of mammalian rRNA genes. Hum. Mol. Genet. 16, R21–R27 (2007).

    CAS  PubMed  Google Scholar 

  106. Rea, S. & Akhtar, A. MSL proteins and the regulation of gene expression. Curr. Top. Microbiol. Immunol. 310, 117–140 (2006).

    CAS  PubMed  Google Scholar 

  107. Rieder, C. L. Ribonucleoprotein staining of centrioles and kinetochores in newt lung cell spindles. J. Cell Biol. 80, 1–9 (1979).

    CAS  PubMed  Google Scholar 

  108. Bouzinba-Segard, H., Guais, A. & Francastel, C. Accumulation of small murine minor satellite transcripts leads to impaired centromeric architecture and function. Proc. Natl Acad. Sci. USA 103, 8709–8714 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. May, B. P., Lippman, Z. B., Fang, Y., Spector, D. L. & Martienssen, R. A. Differential regulation of strand-specific transcripts from Arabidopsis centromeric satellite repeats. PLoS Genet. 1, e79 (2005).

    PubMed Central  PubMed  Google Scholar 

  110. Neumann, P., Yan, H. & Jiang, J. The centromeric retrotransposons of rice are transcribed and differentially processed by RNA interference. Genetics 176, 749–761 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Yan, H. et al. Genomic and genetic characterization of rice Cen3 reveals extensive transcription and evolutionary implications of a complex centromere. Plant Cell 18, 2123–2133 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Saffery, R. et al. Transcription within a functional human centromere. Mol. Cell 12, 509–516 (2003).

    CAS  PubMed  Google Scholar 

  113. Topp, C. N., Zhong, C. X. & Dawe, R. K. Centromere-encoded RNAs are integral components of the maize kinetochore. Proc. Natl Acad. Sci. USA 101, 15986–15991 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Wong, L. H. et al. Centromere RNA is a key component for the assembly of nucleoproteins at the nucleolus and centromere. Genome Res. 17, 1146–1160 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Chen, E. S. et al. Cell cycle control of centromeric repeat transcription and heterochromatin assembly. Nature 451, 734–737 (2008).

    CAS  PubMed  Google Scholar 

  116. Williams, S. K. & Tyler, J. K. Transcriptional regulation by chromatin disassembly and reassembly. Curr. Opin. Genet. Dev. 17, 88–93 (2007).

    CAS  PubMed  Google Scholar 

  117. Reinberg, D. & Sims, R. J. 3rd de FACTo nucleosome dynamics. J. Biol. Chem. 281, 23297–23301 (2006).

    CAS  PubMed  Google Scholar 

  118. Walfridsson, J. et al. The CHD remodeling factor Hrp1 stimulates CENP-A loading to centromeres. Nucleic Acids Res. 33, 2868–2879 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Izuta, H. et al. Comprehensive analysis of the ICEN (Interphase Centromere Complex) components enriched in the CENP-A chromatin of human cells. Genes Cells 11, 673–684 (2006).

    CAS  PubMed  Google Scholar 

  120. Aguilera, A. mRNA processing and genomic instability. Nature Struct. Mol. Biol. 12, 737–738 (2005).

    CAS  Google Scholar 

  121. Zeitlin, S. G., Patel, S., Kavli, B. & Slupphaug, G. Xenopus CENP-A assembly into chromatin requires base excision repair proteins. DNA Repair (Amst.) 4, 760–772 (2005).

    CAS  Google Scholar 

  122. Maggert, K. A. & Karpen, G. H. The activation of a neocentromere in Drosophila requires proximity to an endogenous centromere. Genetics 158, 1615–1628 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Saffery, R. et al. Human centromeres and neocentromeres show identical distribution patterns of >20 functionally important kinetochore-associated proteins. Hum. Mol. Genet. 9, 175–185 (2000).

    CAS  PubMed  Google Scholar 

  124. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thanks members of their laboratories for comments and suggestions. R.C.A. is a Wellcome Trust Principal Research Fellow and his research is supported by the Wellcome Trust (065061/Z). G.H.K.'s work on centromeres is supported by the National Institutes of Health (R01 GM066272).

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Glossary

Kinetochore

Large structure composed of inner and outer regions that contain >80 proteins, which are required for spindle attachment, chromosome movement and regulation of the mitotic checkpoint.

Aneuploidy

Gain or loss of chromosomes, associated with cell and organismal inviability, cancer and birth defects.

Nucleosome

The basic unit of chromatin, containing DNA wrapped around a histone octamer.

Syncytial cells

Cells that contain multiple nuclei, such as preblastoderm Drosophila embryos.

RNA interference

(RNAi). Cellular mechanism involved in gene silencing and 'protection' from retroviral and transposable element invasion. Regulated by proteins such as Dicer and Argonaute, which are responsible for the production of siRNAs that target mRNAs for cleavage and that localize silencing factors to heterochromatic regions.

Dicer

An RNA endonuclease which cleaves double-stranded RNA into siRNAs of approximately 21 bp.

Argonaute

Double-stranded siRNAs are loaded into the Argonaute enzyme; conversion of a double-stranded to a single-stranded siRNA results in activation of the Argonaute. The resident siRNA guides the Argonaute protein to a homologous RNA molecule, allowing the protein to cleave the RNA in the annealed region.

Heterochromatin protein 1

(HP1). Conserved component of silent heterochromatic regions, which contains a chromodomain that binds nucleosomes containing histone H3 that is methylated on lysine 9.

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Allshire, R., Karpen, G. Epigenetic regulation of centromeric chromatin: old dogs, new tricks?. Nat Rev Genet 9, 923–937 (2008). https://doi.org/10.1038/nrg2466

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