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Chromatin remodelling and epigenetic features of germ cells

Abstract

Germ cells have the unique capacity to start a new life upon fertilization. They are generated during a sex-specific differentiation programme called gametogenesis. Maturation of germ cells is characterized by an impressive degree of cellular restructuring and gene regulation that involves remarkable genomic reorganization. These events are finely tuned, but are also susceptible to the introduction of various types of error. Because stable genetic transmission to future generations is essential for life, understanding the control of these processes has far-reaching implications for human health and reproduction.

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Figure 1: Unique chromatin remodelling during the development of male germ cells.
Figure 2: Modifications of histone variants. N-terminal tails of generic histones and some testis-specific variants, with red residues indicating differences.
Figure 3: Germ cells contain various H1 variants.

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References

  1. Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genet. 33 (suppl.), 245–254 (2003)

    Article  CAS  PubMed  Google Scholar 

  2. Cheung, P., Allis, C. D. & Sassone-Corsi, P. Signaling to chromatin through histone modifications. Cell 103, 263–271 (2000)

    Article  CAS  PubMed  Google Scholar 

  3. Fischle, W., Wang, Y. & Allis, C. D. Binary switches and modification cassettes in histone biology and beyond. Nature 425, 475–479 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Felsenfeld, G. & Groudine, M. Controlling the double helix. Nature 421, 448–453 (2003)

    Article  ADS  PubMed  Google Scholar 

  5. Sims, R. J. III, Nishioka, K. & Reinberg, D. Histone lysine methylation: a signature for chromatin function. Trends Genet. 19, 629–639 (2003)

    Article  CAS  PubMed  Google Scholar 

  6. Bannister, A. J., Schneider, R. & Kouzarides, T. Histone methylation: dynamic or static? Cell 109, 801–806 (2002)

    Article  CAS  PubMed  Google Scholar 

  7. Holliday, R. DNA methylation and epigenetic mechanisms. Cell Biophys. 15, 15–20 (1989)

    Article  CAS  PubMed  Google Scholar 

  8. Sassone-Corsi, P. Unique chromatin remodeling and transcriptional regulation in spermatogenesis. Science 296, 2176–2178 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  9. DeBaun, M. R., Niemitz, E. L. & Feinberg, A. P. Association of in vitro fertilization with Beckwith–Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am . J. Hum. Genet. 72, 156–160 (2003)

    Article  CAS  Google Scholar 

  10. Rhind, S. M. et al. Human cloning: can it be made safe? Nature Rev. Genet. 4, 855–864 (2003)

    Article  CAS  PubMed  Google Scholar 

  11. Sarma, K. & Reinberg, D. Histone variants meet their match. Nature Rev. Mol. Cell Biol. 6, 139–149 (2005)

    Article  CAS  Google Scholar 

  12. Marston, A. L. & Amon, A. Meiosis: cell-cycle controls shuffle and deal. Nature Rev. Mol. Cell Biol. 5, 983–997 (2004)

    Article  CAS  Google Scholar 

  13. Meistrich, M. L., Mohapatra, B., Shirley, C. R. & Zhao, M. Roles of transition nuclear proteins in spermiogenesis. Chromosoma 111, 483–488 (2003)

    Article  PubMed  Google Scholar 

  14. Yu, Y. E. et al. Abnormal spermatogenesis and reduced fertility in transition nuclear protein 1-deficient mice. Proc. Natl Acad. Sci. USA 97, 4683–4688 (2000)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhao, M. et al. Targeted disruption of the transition protein 2 gene affects sperm chromatin structure and reduces fertility in mice. Mol. Cell. Biol. 21, 7243–7255 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Meetei, A. R., Ullas, K. S., Vasupradha, V. & Rao, M. R. Involvement of protein kinase A in the phosphorylation of spermatidal protein TP2 and its effect on DNA condensation. Biochemistry 41, 185–195 (2002)

    Article  CAS  PubMed  Google Scholar 

  17. Sung, M. T. & Dixon, G. H. Modification of histones during spermiogenesis in trout: a molecular mechanism for altering histone binding to DNA. Proc. Natl Acad. Sci. USA 67, 1616–1623 (1970)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lahn, B. T. et al. Previously uncharacterized histone acetyltransferases implicated in mammalian spermatogenesis. Proc. Natl Acad. Sci. USA 99, 8707–8712 (2002)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  19. Oliva, R. & Dixon, G. H. Vertebrate protamine genes and the histone-to-protamine replacement reaction. Progr. Nucleic Acid Res. Mol. Biol. 40, 25–94 (1991)

    Article  CAS  Google Scholar 

  20. Lewis, J. D. et al. Histone H1 and the origin of protamines. Proc. Natl Acad. Sci. USA 101, 4148–4152 (2004)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pogany, G. C., Corzett, M., Weston, S. & Balhorn, R. DNA and protein content of mouse sperm. Implications regarding sperm chromatin structure. Exp. Cell Res. 136, 127–136 (1981)

    Article  CAS  PubMed  Google Scholar 

  22. Cho, C. et al. Haploinsufficiency of protamine-1 or -2 causes infertility in mice. Nature Genet. 28, 82–86 (2001)

    CAS  PubMed  Google Scholar 

  23. Wu, J. Y. et al. Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4. Nature Genet. 25, 448–452 (2000)

    Article  CAS  PubMed  Google Scholar 

  24. Xu, X., Toselli, P. A., Russell, L. D. & Seldin, D. C. Globozoospermia in mice lacking the casein kinase IIα′ catalytic subunit. Nature Genet. 23, 118–121 (1999)

    Article  CAS  PubMed  Google Scholar 

  25. Lee, K., Haugen, H. S., Clegg, C. H. & Braun, R. E. Premature translation of protamine 1 mRNA causes precocious nuclear condensation and arrests spermatid differentiation in mice. Proc. Natl Acad. Sci. USA 92, 12451–12455 (1995)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Grimes, S. et al. A rat histone H4 gene closely associated with the testis-specific H1t gene. Exp. Cell Res. 173, 534–545 (1987)

    Article  CAS  PubMed  Google Scholar 

  27. Redon, C. et al. Histone H2A variants H2AX and H2AZ. Curr. Opin. Genet. Dev. 12, 162–169 (2002)

    Article  CAS  PubMed  Google Scholar 

  28. Pandey, N. B. & Marzluff, W. F. The stem-loop structure at the 3′ end of histone mRNA is necessary and sufficient for regulation of histone mRNA stability. Mol. Cell. Biol. 7, 4557–4559 (1987)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Moss, S. B., Challoner, P. B. & Groudine, M. Expression of a novel histone 2B during mouse spermiogenesis. Dev. Biol. 133, 83–92 (1989)

    Article  CAS  PubMed  Google Scholar 

  30. Albig, W. et al. All known human H1 histone genes except the H1(0) gene are clustered on chromosome 6. Genomics 16, 649–654 (1993)

    Article  CAS  PubMed  Google Scholar 

  31. Kobor, M. S. et al. Protein complex containing the conserved Swi2/Snf2-related ATPase Swr1p deposits histone variant H2A.Z into euchromatin. PLoS Biol. 2, E131 (2004)

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. Bramlage, B., Kosciessa, U. & Doenecke, D. Differential expression of the murine histone genes H3.3A and H3.3B. Differentiation 62, 13–20 (1997)

    Article  CAS  PubMed  Google Scholar 

  34. Zalensky, A. O. et al. Human testis/sperm-specific histone H2B (hTSH2B). Molecular cloning and characterization. J. Biol. Chem. 277, 43474–43480 (2002)

    Article  CAS  PubMed  Google Scholar 

  35. Martianov, I. et al. Polar nuclear localization of H1T2, a histone H1 variant, required for spermatid elongation and DNA condensation during spermiogenesis. Proc. Natl Acad. Sci. USA 102, 2808–2813 (2005)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  37. McKittrick, E., Gafken, P. R., Ahmad, K. & Henikoff, S. Histone H3.3 is enriched in covalent modifications associated with active chromatin. Proc. Natl Acad. Sci. USA 101, 1525–1530 (2004)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  38. Crosio, C. et al. Mitotic phosphorylation of histone H3: spatio-temporal regulation by mammalian Aurora kinases. Mol. Cell. Biol. 22, 874–885 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zeitlin, S. G., Shelby, R. D. & Sullivan, K. F. CENP-A is phosphorylated by Aurora B kinase and plays an unexpected role in completion of cytokinesis. J. Cell Biol. 155, 1147–1157 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zalensky, A. O. et al. Human testis/sperm-specific histone H2B (hTSH2B). Molecular cloning and characterization. J. Biol. Chem. 277, 43474–43480 (2002)

    Article  CAS  PubMed  Google Scholar 

  41. Niino, Y. S. et al. PKCφ II, a new isoform of protein kinase C specifically expressed in the seminiferous tubules of mouse testis. J. Biol. Chem. 276, 36711–36717 (2001)

    Article  CAS  PubMed  Google Scholar 

  42. Tseng, T. C., Chen, S. H., Hsu, Y. P. & Tang, T. K. Protein kinase profile of sperm and eggs: cloning and characterization of two novel testis-specific protein kinases (AIE1, AIE2) related to yeast and fly chromosome segregation regulators. DNA Cell Biol. 17, 823–833 (1998)

    Article  CAS  PubMed  Google Scholar 

  43. Park, E. J., Chan, D. W., Park, J. H., Oettinger, M. A. & Kwon, J. DNA-PK is activated by nucleosomes and phosphorylates H2AX within the nucleosomes in an acetylation-dependent manner. Nucleic Acids Res. 31, 6819–6827 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Burma, S., Chen, B. P., Murphy, M., Kurimasa, A. & Chen, D. J. ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J. Biol. Chem. 276, 42462–42467 (2001)

    Article  CAS  PubMed  Google Scholar 

  45. Shroff, R. et al. Distribution and dynamics of chromatin modification induced by a defined DNA double-strand break. Curr. Biol. 14, 1703–1711 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Celeste, A. et al. Genomic instability in mice lacking histone H2AX. Science 296, 922–927 (2002)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  47. Barlow, C. et al. Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I. Development 125, 4007–4017 (1998)

    CAS  PubMed  Google Scholar 

  48. Abraham, R. T. Checkpoint signaling: epigenetic events sound the DNA strand-breaks alarm to the ATM protein kinase. Bioessays 25, 627–630 (2003)

    Article  CAS  PubMed  Google Scholar 

  49. McKee, B. D. & Handel, M. A. Sex chromosomes, recombination, and chromatin conformation. Chromosoma 102, 71–80 (1993)

    Article  CAS  PubMed  Google Scholar 

  50. Chadwick, B. P. & Willard, H. F. Histone H2A variants and the inactive X chromosome: identification of a second macroH2A variant. Hum. Mol. Genet. 10, 1101–1113 (2001)

    Article  CAS  PubMed  Google Scholar 

  51. Baarends, W. M., Roest, H. P. & Grootegoed, J. A. The ubiquitin system in gametogenesis. Mol. Cell. Endocrinol. 151, 5–16 (1999)

    Article  CAS  PubMed  Google Scholar 

  52. Hendzel, M. J., Lever, M. A., Crawford, E. & Th'ng, J. P. The C-terminal domain is the primary determinant of histone H1 binding to chromatin in vivo . J. Biol. Chem. 279, 20028–20034 (2004)

    Article  CAS  PubMed  Google Scholar 

  53. Fantz, D. A. et al. Mice with a targeted disruption of the H1t gene are fertile and undergo normal changes in structural chromosomal proteins during spermiogenesis. Biol. Reprod. 64, 425–431 (2001)

    Article  CAS  PubMed  Google Scholar 

  54. Doenecke, D. et al. Histone gene expression and chromatin structure during spermatogenesis. Adv. Exp. Med. Biol. 424, 37–48 (1997)

    Article  CAS  PubMed  Google Scholar 

  55. Nayernia, K. et al. Male mice lacking three germ cell expressed genes are fertile. Biol. Reprod. 69, 1973–1978 (2003)

    Article  CAS  PubMed  Google Scholar 

  56. Yan, W., Ma, L., Burns, K. H. & Matzuk, M. M. HILS1 is a spermatid-specific linker histone H1-like protein implicated in chromatin remodeling during mammalian spermiogenesis. Proc. Natl Acad. Sci. USA 100, 10546–10551 (2003)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  57. Contreras, A. et al. The dynamic mobility of histone H1 is regulated by cyclin/CDK phosphorylation. Mol. Cell. Biol. 23, 8626–8636 (2003)

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kuzmichev, A., Jenuwein, T., Tempst, P. & Reinberg, D. Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3. Mol. Cell 14, 183–193 (2004)

    Article  CAS  PubMed  Google Scholar 

  59. Kim, J. M., Liu, H., Tazaki, M., Nagata, M. & Aoki, F. Changes in histone acetylation during mouse oocyte meiosis. J. Cell Biol. 7, 37–46 (2003)

    Article  Google Scholar 

  60. De La Fuente, R., Viveiros, M. M., Wigglesworth, K. & Eppig, J. J. ATRX, a member of the SNF2 family of helicase/ATPases, is required for chromosome alignment and meiotic spindle organization in metaphase II stage mouse oocytes. Dev. Biol. 272, 1–14 (2004)

    Article  CAS  PubMed  Google Scholar 

  61. Jedrusik, M. A. & Schulze, E. A single histone H1 isoform (H1.1) is essential for chromatin silencing and germline development in Caenorhabditis elegans . Development 128, 1069–1080 (2001)

    CAS  PubMed  Google Scholar 

  62. Clarke, H. J., Bustin, M. & Oblin, C. Chromatin modifications during oogenesis in the mouse: removal of somatic subtypes of histone H1 from oocyte chromatin occurs post-natally through a post-transcriptional mechanism. J. Cell Sci. 110, 477–487 (1997)

    CAS  PubMed  Google Scholar 

  63. Debey, P. et al. Competent mouse oocytes isolated from antral follicles exhibit different chromatin organization and follow different maturation dynamics. Mol. Reprod. Dev. 36, 59–74 (1993)

    Article  CAS  PubMed  Google Scholar 

  64. Teranishi, T. et al. Rapid replacement of somatic linker histones with the oocyte-specific linker histone H1Foo in nuclear transfer. Dev. Biol. 266, 76–86 (2004)

    Article  CAS  PubMed  Google Scholar 

  65. Buaas, F. W. et al. Plzf is required in adult male germ cells for stem cell self-renewal. Nature Genet. 36, 647–652 (2004)

    Article  CAS  PubMed  Google Scholar 

  66. Costoya, J. A. et al. Essential role of Plzf in maintenance of spermatogonial stem cells. Nature Genet. 36, 653–659 (2004)

    Article  CAS  PubMed  Google Scholar 

  67. Peters, A. H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323–337 (2001)

    Article  CAS  PubMed  Google Scholar 

  68. Sedgwick, B. Repairing DNA-methylation damage. Nature Rev. Mol. Cell Biol. 5, 148–157 (2004)

    Article  CAS  Google Scholar 

  69. Roest, H. P. et al. Inactivation of the HR6B ubiquitin-conjugating DNA repair enzyme in mice causes male sterility associated with chromatin modification. Cell 86, 799–810 (1996)

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  71. Hay, B., Ackerman, L., Barbel, S., Jan, L. Y. & Jan, Y. N. Identification of a component of Drosophila polar granules. Development 103, 625–640 (1988)

    CAS  PubMed  Google Scholar 

  72. Toyooka, Y. et al. Expression and intracellular localization of mouse Vasa-homologue protein during germ cell development. Mech. Dev. 93, 139–149 (2000)

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  74. Pivot-Pajot, C. et al. Acetylation-dependent chromatin reorganization by BRDT, a testis-specific bromodomain-containing protein. Mol. Cell. Biol. 23, 5354–5365 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hazzouri, M. et al. Regulated hyperacetylation of core histones during mouse spermatogenesis: involvement of histone deacetylases. Eur. J. Cell Biol. 79, 950–960 (2000)

    Article  CAS  PubMed  Google Scholar 

  76. Brinster, R. L. Germline stem cell transplantation and transgenesis. Science 296, 2174–2176 (2002)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  77. Waterland, R. A. & Jirtle, R. L. Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition 20, 63–68 (2004)

    Article  CAS  PubMed  Google Scholar 

  78. Moss, S. B. & Orth, J. M. Localization of a spermatid-specific histone 2B protein in mouse spermiogenic cells. Biol. Reprod. 48, 1047–1056 (1993)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We were unfortunately unable to include all the relevant references owing to space constraints. We are grateful to C. D. Allis, D. Reinberg, R. Jaenisch, E. Borrelli, I. Davidson, N. Kotaja, U. Kolthur, G. Fienga, K. Hogeveen, C. Krausz, M. Parvinen, S. Henikoff, R. L. Brinster and all members of the Sassone-Corsi laboratory for critical reading of the manuscript, advice and stimulating discussions. S.K. is supported by fellowships from the Fondation pour la Recherche Médicale and the Marie Curie Programme.

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Kimmins, S., Sassone-Corsi, P. Chromatin remodelling and epigenetic features of germ cells. Nature 434, 583–589 (2005). https://doi.org/10.1038/nature03368

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