Science China Life Sciences

, Volume 55, Issue 8, pp 670–676 | Cite as

Epigenetic changes associated with oocyte aging

  • XingWei Liang
  • JunYu Ma
  • Heide Schatten
  • QingYuan Sun
Open Access
Review Special Topic


It is well established that the decline in female reproductive outcomes is related to postovulatory aging of oocytes and advanced maternal age. Poor oocyte quality is correlated with compromised genetic integrity and epigenetic changes during the oocyte aging process. Here, we review the epigenetic alterations, mainly focused on DNA methylation, histone acetylation and methylation associated with postovulatory oocyte aging as well as advanced maternal age. Furthermore, we address the underlying epigenetic mechanisms that contribute to the decline in oocyte quality during oocyte aging.


fertility advanced maternal age postovulatory oocyte aging DNA methylation histone modification 


  1. 1.
    Jones K T. Meiosis in oocytes: predisposition to aneuploidy and its increased incidence with age. Hum Reprod Update, 2008, 14: 143–158PubMedCrossRefGoogle Scholar
  2. 2.
    Wang Z B, Schatten H, Sun Q Y. Why is chromosome segregation error in oocytes increased with maternal aging? Physiology (Bethesda), 2011, 26: 314–325CrossRefGoogle Scholar
  3. 3.
    Wang Q, Sun Q Y. Evaluation of oocyte quality: morphological, cellular and molecular predictors. Reprod Fertil Dev, 2007, 19: 1–12PubMedCrossRefGoogle Scholar
  4. 4.
    Austin C R. In: Whittaher J R, ed. Concepts of Development. Sinauer Associates Inc., 1974Google Scholar
  5. 5.
    Kikuchi K, Naito K, Noguchi J, et al. Maturation/M-phase promoting factor: a regulator of aging in porcine oocytes. Biol Reprod, 2000, 63: 715–722PubMedCrossRefGoogle Scholar
  6. 6.
    Miao Y L, Kikuchi K, Sun Q Y, et al. Oocyte aging: cellular and molecular changes, developmental potential and reversal possibility. Hum Reprod Update, 2009, 15: 573–585PubMedCrossRefGoogle Scholar
  7. 7.
    Tatone C, Amicarelli F, Carbone M C, et al. Cellular and molecular aspects of ovarian follicle aging. Hum Reprod Update, 2008, 14: 131–142PubMedCrossRefGoogle Scholar
  8. 8.
    Ma J Y, Liang X W, Schatten H, et al. Active DNA demethylation in mammalian preimplantation embryos: new insights and new perspectives. Mol Hum Reprod, 2012, 18: 333–340PubMedCrossRefGoogle Scholar
  9. 9.
    Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science, 2001, 293: 1089–1093PubMedCrossRefGoogle Scholar
  10. 10.
    Verona R I, Mann M R, Bartolomei M S. Genomic imprinting: intricacies of epigenetic regulation in clusters. Annu Rev Cell Dev Biol, 2003, 19: 237–259PubMedCrossRefGoogle Scholar
  11. 11.
    Bartolomei M S, Ferguson-Smith A C. Mammalian genomic imprinting. Cold Spring Harb Perspect Biol, 2011, 3: a002592PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature, 2007, 447: 425–432PubMedCrossRefGoogle Scholar
  13. 13.
    Hiura H, Obata Y, Komiyama J, et al. Oocyte growth-dependent progression of maternal imprinting in mice. Genes Cells, 2006, 11: 353–361PubMedCrossRefGoogle Scholar
  14. 14.
    La Salle S, Mertineit C, Taketo T, et al. Windows for sex-specific methylation marked by DNA methyltransferase expression profiles in mouse germ cells. Dev Biol, 2004, 268: 403–415PubMedCrossRefGoogle Scholar
  15. 15.
    Lucifero D, La Salle S, Bourc’his D, et al. Coordinate regulation of DNA methyltransferase expression during oogenesis. BMC Dev Biol, 2007, 7: 36PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Lucifero D, Mann M R, Bartolomei M S, et al. Gene-specific timing and epigenetic memory in oocyte imprinting. Hum Mol Genet, 2004, 13: 839–849PubMedCrossRefGoogle Scholar
  17. 17.
    Bestor T H. The DNA methyltransferases of mammals. Hum Mol Genet, 2000, 9: 2395–2402PubMedCrossRefGoogle Scholar
  18. 18.
    Branco M R, Oda M, Reik W. Safeguarding parental identity: Dnmt1 maintains imprints during epigenetic reprogramming in early embryogenesis. Genes Dev, 2008, 22: 1567–1571PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Allfrey V G, Faulkner R, Mirsky A E. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc Natl Acad Sci USA, 1964, 51: 786–794PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Gutierrez R M, Hnilica L S. Tissue specificity of histone phosphorylation. Science, 1967, 157: 1324–1325PubMedCrossRefGoogle Scholar
  21. 21.
    Huletsky A, Niedergang C, Frechette A, et al. Sequential ADP-ribosylation pattern of nucleosomal histones. ADP-ribosylation of nucleosomal histones. Eur J Biochem, 1985, 146: 277–285PubMedCrossRefGoogle Scholar
  22. 22.
    Nathan D, Ingvarsdottir K, Sterner D E, et al. Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications. Genes Dev, 2006, 20: 966–976PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Koprinarova M A, Russev G C. Dynamics of histone H4 acetylation during the cell cycle. Cell Cycle, 2008, 7: 414–416PubMedCrossRefGoogle Scholar
  24. 24.
    Rada-Iglesias A, Enroth S, Andersson R, et al. Histone H3 lysine 27 trimethylation in adult differentiated colon associated to cancer DNA hypermethylation. Epigenetics, 2009, 4: 107–113PubMedCrossRefGoogle Scholar
  25. 25.
    Xu D, Bai J, Duan Q, et al. Covalent modifications of histones during mitosis and meiosis. Cell Cycle, 2009, 8: 3688–3694PubMedCrossRefGoogle Scholar
  26. 26.
    Kouzarides T. Chromatin modifications and their function. Cell, 2007, 128: 693–705PubMedCrossRefGoogle Scholar
  27. 27.
    Strahl B D, Allis C D. The language of covalent histone modifications. Nature, 2000, 403: 41–45PubMedCrossRefGoogle Scholar
  28. 28.
    Wang N, Tilly J L. Epigenetic status determines germ cell meiotic commitment in embryonic and postnatal mammalian gonads. Cell Cycle, 2010, 9: 339–349PubMedCrossRefGoogle Scholar
  29. 29.
    Gu L, Wang Q, Sun Q Y. Histone modifications during mammalian oocyte maturation: dynamics, regulation and functions. Cell Cycle, 2010, 9: 1942–1950PubMedCrossRefGoogle Scholar
  30. 30.
    Jiang G J, Wang K, Miao D Q, et al. Protein profile changes during porcine oocyte aging and effects of caffeine on protein expression patterns. PLoS ONE, 2011, 6: e28996PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Yue M X, Fu X W, Zhou G B, et al. Abnormal DNA methylation in oocytes could be associated with a decrease in reproductive potential in old mice. J Assist Reprod Genet, 2012, 29: 643–650PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Lopes F L, Fortier A L, Darricarrere N, et al. Reproductive and epigenetic outcomes associated with aging mouse oocytes. Hum Mol Genet, 2009, 18: 2032–2044PubMedCrossRefGoogle Scholar
  33. 33.
    Holinka C F, Tseng Y C, Finch C E. Reproductive aging in C57BL/6J mice: plasma progesterone, viable embryos and resorption frequency throughout pregnancy. Biol Reprod, 1979, 20: 1201–1211PubMedCrossRefGoogle Scholar
  34. 34.
    Manosalva I, Gonzalez A. Aging changes the chromatin configuration and histone methylation of mouse oocytes at germinal vesicle stage. Theriogenology, 2010, 74: 1539–1547PubMedCrossRefGoogle Scholar
  35. 35.
    Ooga M, Inoue A, Kageyama S, et al. Changes in H3K79 methylation during preimplantation development in mice. Biol Reprod, 2008, 78: 413–424PubMedCrossRefGoogle Scholar
  36. 36.
    Park K E, Magnani L, Cabot R A. Differential remodeling of mono- and trimethylated H3K27 during porcine embryo development. Mol Reprod Dev, 2009, 76: 1033–1042PubMedCrossRefGoogle Scholar
  37. 37.
    Hou J, Liu L, Zhang J, et al. Epigenetic modification of histone 3 at lysine 9 in sheep zygotes and its relationship with DNA methylation. BMC Dev Biol, 2008, 8: 60PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Racedo S E, Wrenzycki C, Lepikhov K, et al. Epigenetic modifications and related mRNA expression during bovine oocyte in vitro maturation. Reprod Fertil Dev, 2009, 21: 738–748PubMedCrossRefGoogle Scholar
  39. 39.
    Qiao J, Chen Y, Yan L Y, et al. Changes in histone methylation during human oocyte maturation and IVF-or ICSI-derived embryo development. Fertil Steril, 2010, 93: 1628–1636PubMedCrossRefGoogle Scholar
  40. 40.
    Akiyama T, Nagata M, Aoki F. Inadequate histone deacetylation during oocyte meiosis causes aneuploidy and embryo death in mice. Proc Natl Acad Sci USA, 2006, 103: 7339–7344PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Manosalva I, Gonzalez A. Aging alters histone H4 acetylation and CDC2A in mouse germinal vesicle stage oocytes. Biol Reprod, 2009, 81: 1164–1171PubMedCrossRefGoogle Scholar
  42. 42.
    van den Berg I M, Eleveld C, van der Hoeven M, et al. Defective deacetylation of histone 4 K12 in human oocytes is associated with advanced maternal age and chromosome misalignment. Hum Reprod, 2011, 26: 1181–1190PubMedCrossRefGoogle Scholar
  43. 43.
    Lucifero D, Mertineit C, Clarke H J, et al. Methylation dynamics of imprinted genes in mouse germ cells. Genomics, 2002, 79: 530–538PubMedCrossRefGoogle Scholar
  44. 44.
    Li J Y, Lees-Murdock D J, Xu G L, et al. Timing of establishment of paternal methylation imprints in the mouse. Genomics, 2004, 84: 952–960PubMedCrossRefGoogle Scholar
  45. 45.
    Liang X W, Zhu J Q, Miao Y L, et al. Loss of methylation imprint of SNRPN in postovulatory aging mouse oocyte. Biochem Biophys Res Commun, 2008, 371: 16–21PubMedCrossRefGoogle Scholar
  46. 46.
    Imamura T, Kerjean A, Heams T, et al. Dynamic CpG and non-CpG methylation of the Peg1/Mest gene in the mouse oocyte and preimplantation embryo. J Biol Chem, 2005, 280: 20171–20175PubMedCrossRefGoogle Scholar
  47. 47.
    Tarin J J, Perez-Albala S, Aguilar A, et al. Long-term effects of postovulatory aging of mouse oocytes on offspring: a two-generational study. Biol Reprod, 1999, 61: 1347–1355PubMedCrossRefGoogle Scholar
  48. 48.
    Tarin J J, Perez-Albala S, Perez-Hoyos S, et al. Postovulatory aging of oocytes decreases reproductive fitness and longevity of offspring. Biol Reprod, 2002, 66: 495–499PubMedCrossRefGoogle Scholar
  49. 49.
    Liang X W, Ge Z J, Guo L, et al. Effect of postovulatory oocyte aging on DNA methylation imprinting acquisition in offspring oocytes. Fertil Steril, 2011, 96: 1479–1484PubMedCrossRefGoogle Scholar
  50. 50.
    Huang J C, Yan L Y, Lei Z L, et al. Changes in histone acetylation during postovulatory aging of mouse oocyte. Biol Reprod, 2007, 77: 666–670PubMedCrossRefGoogle Scholar
  51. 51.
    Liu N, Wu Y G, Lan G C, et al. Pyruvate prevents aging of mouse oocytes. Reproduction, 2009, 138: 223–234PubMedCrossRefGoogle Scholar
  52. 52.
    Cui M S, Wang X L, Tang D W, et al. Acetylation of H4K12 in porcine oocytes during in vitro aging: potential role of ooplasmic reactive oxygen species. Theriogenology, 2011, 75: 638–646PubMedCrossRefGoogle Scholar
  53. 53.
    Yoshida M, Kijima M, Akita M, et al. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem, 1990, 265: 17174–17179PubMedGoogle Scholar
  54. 54.
    De La Fuente R, Viveiros M M, Wigglesworth K, et al. 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, 2004, 272: 1–14CrossRefGoogle Scholar
  55. 55.
    Wang Q, Yin S, Ai J S, et al. Histone deacetylation is required for orderly meiosis. Cell Cycle, 2006, 5: 766–774PubMedCrossRefGoogle Scholar
  56. 56.
    Pan H, Ma P, Zhu W, et al. Age-associated increase in aneuploidy and changes in gene expression in mouse eggs. Dev Biol, 2008, 316: 397–407PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Hamatani T, Falco G, Carter M G, et al. Age-associated alteration of gene expression patterns in mouse oocytes. Hum Mol Genet, 2004, 13: 2263–2278PubMedCrossRefGoogle Scholar
  58. 58.
    Ratnam S, Mertineit C, Ding F, et al. Dynamics of Dnmt1 methyltransferase expression and intracellular localization during oogenesis and preimplantation development. Dev Biol, 2002, 245: 304–314PubMedCrossRefGoogle Scholar
  59. 59.
    Hirasawa R, Chiba H, Kaneda M, et al. Maternal and zygotic Dnmt1 are necessary and sufficient for the maintenance of DNA methylation imprints during preimplantation development. Genes Dev, 2008, 22: 1607–1616PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Kurihara Y, Kawamura Y, Uchijima Y, et al. Maintenance of genomic methylation patterns during preimplantation development requires the somatic form of DNA methyltransferase 1. Dev Biol, 2008, 313: 335–346PubMedCrossRefGoogle Scholar
  61. 61.
    Mohan K N, Ding F, Chaillet J R. Distinct roles of DMAP1 in mouse development. Mol Cell Biol, 2011, 31: 1861–1869PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Zhang L, Lu D Y, Ma W Y, et al. Age-related changes in the localization of DNA methyltransferases during meiotic maturation in mouse oocytes. Fertil Steril, 2011, 95: 1531–1534PubMedCrossRefGoogle Scholar
  63. 63.
    Lees-Murdock D J, Shovlin T C, Gardiner T, et al. DNA methyltransferase expression in the mouse germ line during periods of de novo methylation. Dev Dyn, 2005, 232: 992–1002PubMedCrossRefGoogle Scholar
  64. 64.
    Wood A J, Oakey R J. Genomic imprinting in mammals: emerging themes and established theories. PLoS Genet, 2006, 2: e147PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Suo L, Meng Q G, Pei Y, et al. Changes in acetylation on lysine 12 of histone H4 (acH4K12) of murine oocytes during maternal aging may affect fertilization and subsequent embryo development. Fertil Steril, 2010, 93: 945–951PubMedCrossRefGoogle Scholar
  66. 66.
    Yu J N, Wang M, Wang D Q, et al. Chromosome changes of aged oocytes after ovulation. Yi Chuan, 2007, 29: 225–229PubMedCrossRefGoogle Scholar

Copyright information

© The Author(s) 2012

Authors and Affiliations

  • XingWei Liang
    • 1
    • 2
  • JunYu Ma
    • 1
  • Heide Schatten
    • 3
  • QingYuan Sun
    • 1
  1. 1.State Key Laboratory of Reproductive Biology, Institute of ZoologyChinese Academy of SciencesBeijingChina
  2. 2.Department of Animal SciencesChungbuk National UniversityCheongjuRepublic of Korea
  3. 3.Department of Veterinary PathobiologyUniversity of MissouriColumbiaUSA

Personalised recommendations