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The Sperm Epigenome: Implications for Assisted Reproductive Technologies

  • Douglas T. CarrellEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1166)

Abstract

Compared to other cells, sperm undergo dramatic remodeling of their chromatin during late spermiogenesis in which approximately 95% of histones are removed and replaced with protamines. Despite this large-scale remodeling, key developmental genes, some miRNA genes, and imprinted genes retain their association with histone. The developmental genes have a unique epigenetic signature, termed bivalency, that poises the genes for embryonic activation. Anomalies in that epigenetic poising signature, either in the form of DNA methylation aberrations, improper protamination, or altered histone modifications, are associated with infertility and reduced embryogenesis capability. Additionally, some small noncoding RNAs are retained, while others are actively added to the sperm and appear to affect embryogenesis. Therefore, initial studies have begun to formulate pathways by which the sperm epigenome can be used as a diagnostic tool in the clinic. While in their infancy, these assays likely portend improved diagnostics and added information for patients and clinicians. Recent studies also highlight the possibility that the sperm epigenome can be used to evaluate lifestyle and environmental risks to the patient and potentially to the offspring.

Keywords

ART Embryogenesis Epigenetics DNA methylation Histones Small RNAs Environment 

References

  1. Abbasi M, Smith AD, Swaminathan H, Sangngern P, Douglas A, Horsager A, Carrell DT, Uren PJ (2018) Establishing a stable, repeatable platform for measuring changes in sperm DNA methylation. Clin Epigenetics 10(1):119.  https://doi.org/10.1186/s13148-018-0551-7CrossRefPubMedPubMedCentralGoogle Scholar
  2. Ankolkar M et al (2012) Methylation analysis of idiopathic recurrent spontaneous miscarriage cases reveals aberrant imprinting at H19 ICR in normozoospermic individuals. Fertil Steril 98:1186–1192.  https://doi.org/10.1016/j.fertnstert.2012.07.1143CrossRefPubMedGoogle Scholar
  3. Aoki VW, Liu L, Carrell DT (2005) Identification and evaluation of a novel sperm protamine abnormality in a population of infertile males. Hum Reprod 20:1298–1306.  https://doi.org/10.1093/humrep/deh798CrossRefPubMedGoogle Scholar
  4. Aoki VW et al (2006a) Sperm protamine 1/protamine 2 ratios are related to in vitro fertilization pregnancy rates and predictive of fertilization ability. Fertil Steril 86:1408–1415.  https://doi.org/10.1016/j.fertnstert.2006.04.024CrossRefPubMedGoogle Scholar
  5. Aoki VW, Emery BR, Liu L, Carrell DT (2006b) Protamine levels vary between individual sperm cells of infertile human males and correlate with viability and DNA integrity. J Androl 27:890–898.  https://doi.org/10.2164/jandrol.106.000703CrossRefPubMedGoogle Scholar
  6. Aoki VW, Liu L, Carrell DT (2006c) A novel mechanism of protamine expression deregulation highlighted by abnormal protamine transcript retention in infertile human males with sperm protamine deficiency. Mol Hum Reprod 12:41–50.  https://doi.org/10.1093/molehr/gah258CrossRefPubMedGoogle Scholar
  7. Aston KI, Punj V, Liu L, Carrell DT (2012) Genome-wide sperm deoxyribonucleic acid methylation is altered in some men with abnormal chromatin packaging or poor in vitro fertilization embryogenesis. Fertil Steril 97:285–292.  https://doi.org/10.1016/j.fertnstert.2011.11.008CrossRefPubMedGoogle Scholar
  8. Aston KI et al (2015) Aberrant sperm DNA methylation predicts male fertility status and embryo quality. Fertil Steril 104:1388–1397 e1381–1385.  https://doi.org/10.1016/j.fertnstert.2015.08.019CrossRefPubMedGoogle Scholar
  9. Barbosa TD et al (2015) Paternal chronic high-fat diet consumption reprogrammes the gametic epigenome and induces transgenerational inheritance of metabolic disorder. Diabetologia 58:S162–S163Google Scholar
  10. Beck D, Sadler-Riggleman I, Skinner MK (2017) Generational comparisons (F1 versus F3) of vinclozolin induced epigenetic transgenerational inheritance of sperm differential DNA methylation regions (epimutations) using MeDIP-Seq. Environ Epigenet 3.  https://doi.org/10.1093/eep/dvx016
  11. Carone BR et al (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143:1084–1096.  https://doi.org/10.1016/j.cell.2010.12.008CrossRefPubMedPubMedCentralGoogle Scholar
  12. Carrell DT (2012) Epigenetics of the male gamete. Fertil Steril 97:267–274.  https://doi.org/10.1016/j.fertnstert.2011.12.036CrossRefPubMedGoogle Scholar
  13. Carrell DT, Liu L (2001) Altered protamine 2 expression is uncommon in donors of known fertility, but common among men with poor fertilizing capacity, and may reflect other abnormalities of spermiogenesis. J Androl 22:604–610PubMedGoogle Scholar
  14. Carrell DT, Emery BR, Hammoud S (2008) The aetiology of sperm protamine abnormalities and their potential impact on the sperm epigenome. Int J Androl 31:537–545.  https://doi.org/10.1111/j.1365-2605.2008.00872.xCrossRefPubMedGoogle Scholar
  15. Chen Q et al (2016) Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351:397–400.  https://doi.org/10.1126/science.aad7977CrossRefPubMedGoogle Scholar
  16. Cho C et al (2003) Protamine 2 deficiency leads to sperm DNA damage and embryo death in mice. Biol Reprod 69:211–217.  https://doi.org/10.1095/biolreprod.102.015115CrossRefPubMedGoogle Scholar
  17. Conine CC, Sun F, Song L, Rivera-Pérez JA, Rando OJ (2018) Small RNAs gained during epididymal transit of sperm are essential for embryonic development in mice. Dev Cell 46:470–480.e473.  https://doi.org/10.1016/j.devcel.2018.06.024CrossRefPubMedGoogle Scholar
  18. Cox GF et al (2002) Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am J Hum Genet 71:162–164.  https://doi.org/10.1086/341096CrossRefPubMedPubMedCentralGoogle Scholar
  19. Deans C, Maggert KA (2015) What do you mean, “epigenetic”? Genetics 199:887–896.  https://doi.org/10.1534/genetics.114.173492CrossRefPubMedPubMedCentralGoogle Scholar
  20. Denomme MM, McCallie BR, Parks JC, Schoolcraft WB, Katz-Jaffe MG (2017) Alterations in the sperm histone-retained epigenome are associated with unexplained male factor infertility and poor blastocyst development in donor oocyte IVF cycles. Hum Reprod 32:2443–2455.  https://doi.org/10.1093/humrep/dex317CrossRefPubMedGoogle Scholar
  21. Denomme MM et al (2018) Inheritance of epigenetic dysregulation from male factor infertility has a direct impact on reproductive potential. Fertil Steril 110:419–428 e411.  https://doi.org/10.1016/j.fertnstert.2018.04.004CrossRefPubMedGoogle Scholar
  22. Dere E et al (2018) Effects of continuous bisphenol A exposure from early gestation on 90day old rat testes function and sperm molecular profiles: a CLARITY-BPA consortium study. Toxicol Appl Pharmacol 347:1–9.  https://doi.org/10.1016/j.taap.2018.03.021CrossRefPubMedPubMedCentralGoogle Scholar
  23. Gannon JR, Emery BR, Jenkins TG, Carrell DT (2014) The sperm epigenome: implications for the embryo. Adv Exp Med Biol 791:53–66.  https://doi.org/10.1007/978-1-4614-7783-9_4CrossRefPubMedGoogle Scholar
  24. Guibert S, Forne T, Weber M (2012) Global profiling of DNA methylation erasure in mouse primordial germ cells. Genome Res 22:633–641.  https://doi.org/10.1101/gr.130997.111CrossRefPubMedPubMedCentralGoogle Scholar
  25. Hammoud S, Liu L, Carrell DT (2009a) Protamine ratio and the level of histone retention in sperm selected from a density gradient preparation. Andrologia 41:88–94.  https://doi.org/10.1111/j.1439-0272.2008.00890.xCrossRefPubMedGoogle Scholar
  26. Hammoud SS et al (2009b) Distinctive chromatin in human sperm packages genes for embryo development. Nature 460:473–478.  https://doi.org/10.1038/nature08162CrossRefPubMedPubMedCentralGoogle Scholar
  27. Hammoud SS, Purwar J, Pflueger C, Cairns BR, Carrell DT (2010) Alterations in sperm DNA methylation patterns at imprinted loci in two classes of infertility. Fertil Steril 94:1728–1733.  https://doi.org/10.1016/j.fertnstert.2009.09.010CrossRefPubMedGoogle Scholar
  28. Hammoud SS et al (2011) Genome-wide analysis identifies changes in histone retention and epigenetic modifications at developmental and imprinted gene loci in the sperm of infertile men. Hum Reprod 26:2558–2569.  https://doi.org/10.1093/humrep/der192CrossRefPubMedPubMedCentralGoogle Scholar
  29. Harvey W (1651) Exercitationes de generatione animalium. Typis, LondonGoogle Scholar
  30. Harvey W (1653) Anatomical exercitations concerning the generation of living creatures to which are added particular discourses of births and of conceptions, &c. (James Young, for Octavian Pulleyn)Google Scholar
  31. Heijmans BT et al (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A 105:17046–17049.  https://doi.org/10.1073/pnas.0806560105CrossRefPubMedPubMedCentralGoogle Scholar
  32. Holliday R (2006) Epigenetics: a historical overview. Epigenetics 1:76–80CrossRefGoogle Scholar
  33. Illum LRH, Bak ST, Lund S, Nielsen AL (2018) DNA methylation in epigenetic inheritance of metabolic diseases through the male germ line. J Mol Endocrinol 60:R39–R56.  https://doi.org/10.1530/JME-17-0189CrossRefPubMedGoogle Scholar
  34. Jenkins TG, Carrell DT (2011) The paternal epigenome and embryogenesis: poising mechanisms for development. Asian J Androl 13:76–80.  https://doi.org/10.1038/aja.2010.61CrossRefPubMedGoogle Scholar
  35. Jenkins TG, Aston KI, Cairns BR, Carrell DT (2013) Paternal aging and associated intraindividual alterations of global sperm 5-methylcytosine and 5-hydroxymethylcytosine levels. Fertil Steril 100:945–951.  https://doi.org/10.1016/j.fertnstert.2013.05.039CrossRefPubMedGoogle Scholar
  36. Jenkins TG, Aston KI, Pflueger C, Cairns BR, Carrell DT (2014) Age-associated sperm DNA methylation alterations: possible implications in offspring disease susceptibility. PLoS Genet 10:e1004458.  https://doi.org/10.1371/journal.pgen.1004458CrossRefPubMedPubMedCentralGoogle Scholar
  37. Jenkins TG et al (2016a) Teratozoospermia and asthenozoospermia are associated with specific epigenetic signatures. Andrology 4:843–849.  https://doi.org/10.1111/andr.12231CrossRefPubMedGoogle Scholar
  38. Jenkins TG et al (2016b) Decreased fecundity and sperm DNA methylation patterns. Fertil Steril 105:51–57 e51–53.  https://doi.org/10.1016/j.fertnstert.2015.09.013CrossRefPubMedGoogle Scholar
  39. Jenkins TG, Aston KI, James ER, Carrell DT (2017) Sperm epigenetics in the study of male fertility, offspring health, and potential clinical applications. Syst Biol Reprod Med 63:69–76.  https://doi.org/10.1080/19396368.2016.1274791CrossRefPubMedGoogle Scholar
  40. Jenkins TG, Aston KI, Carrell DT (2018) Sperm epigenetics and aging. Transl Androl Urol 7:S328–S335.  https://doi.org/10.21037/tau.2018.06.10CrossRefPubMedPubMedCentralGoogle Scholar
  41. Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080.  https://doi.org/10.1126/science.1063127CrossRefPubMedGoogle Scholar
  42. Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev Genet 8:253–262.  https://doi.org/10.1038/nrg2045CrossRefPubMedPubMedCentralGoogle Scholar
  43. Jodar M et al (2015) Absence of sperm RNA elements correlates with idiopathic male infertility. Sci Transl Med 7:295re296.  https://doi.org/10.1126/scitranslmed.aab1287CrossRefGoogle Scholar
  44. Karaca MZ et al (2017) Association between methylenetetrahydrofolate reductase (MTHFR) gene promoter hypermethylation and the risk of idiopathic male infertility. Andrologia 49(7).  https://doi.org/10.1111/and.12698CrossRefGoogle Scholar
  45. Kobayashi H et al (2007) Aberrant DNA methylation of imprinted loci in sperm from oligospermic patients. Hum Mol Genet 16:2542–2551.  https://doi.org/10.1093/hmg/ddm187CrossRefPubMedGoogle Scholar
  46. Krawetz SA et al (2011) A survey of small RNAs in human sperm. Hum Reprod 26:3401–3412.  https://doi.org/10.1093/humrep/der329CrossRefPubMedPubMedCentralGoogle Scholar
  47. Laqqan M, Hammadeh ME (2018) Aberrations in sperm DNA methylation patterns of males suffering from reduced fecundity. Andrologia 50(3).  https://doi.org/10.1111/and.12913CrossRefGoogle Scholar
  48. Le Bouc Y et al (2010) Epigenetics, genomic imprinting and assisted reproductive technology. Ann Endocrinol (Paris) 71:237–238.  https://doi.org/10.1016/j.ando.2010.02.004CrossRefGoogle Scholar
  49. Liu WM et al (2012) Sperm-borne microRNA-34c is required for the first cleavage division in mouse. Proc Natl Acad Sci U S A 109:490–494.  https://doi.org/10.1073/pnas.1110368109CrossRefPubMedGoogle Scholar
  50. Lu Z et al (2018) Urine mercury levels correlate with DNA methylation of imprinting gene H19 in the sperm of reproductive-aged men. PLoS One 13:e0196314.  https://doi.org/10.1371/journal.pone.0196314CrossRefPubMedPubMedCentralGoogle Scholar
  51. Messerschmidt DM, Knowles BB, Solter D (2014) DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos. Genes Dev 28:812–828.  https://doi.org/10.1101/gad.234294.113CrossRefPubMedPubMedCentralGoogle Scholar
  52. Murphy PJ, Wu SF, James CR, Wike CL, Cairns BR (2018a) Placeholder nucleosomes underlie germline-to-embryo DNA methylation reprogramming. Cell 172:993–1006 e1013.  https://doi.org/10.1016/j.cell.2018.01.022CrossRefPubMedGoogle Scholar
  53. Murphy SK et al (2018b) Cannabinoid exposure and altered DNA methylation in rat and human sperm. Epigenetics 13:1208.  https://doi.org/10.1080/15592294.2018.1554521CrossRefPubMedGoogle Scholar
  54. Nanassy L, Carrell DT (2011) Abnormal methylation of the promoter of CREM is broadly associated with male factor infertility and poor sperm quality but is improved in sperm selected by density gradient centrifugation. Fertil Steril 95:2310–2314.  https://doi.org/10.1016/j.fertnstert.2011.03.096CrossRefPubMedGoogle Scholar
  55. Ng SF et al (2010) Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467:963–966.  https://doi.org/10.1038/nature09491CrossRefPubMedGoogle Scholar
  56. Ostermeier GC, Dix DJ, Miller D, Khatri P, Krawetz SA (2002) Spermatozoal RNA profiles of normal fertile men. Lancet 360:772–777.  https://doi.org/10.1016/S0140-6736(02)09899-9CrossRefPubMedGoogle Scholar
  57. Ostermeier GC, Miller D, Huntriss JD, Diamond MP, Krawetz SA (2004) Reproductive biology: delivering spermatozoan RNA to the oocyte. Nature 429:154.  https://doi.org/10.1038/429154aCrossRefPubMedGoogle Scholar
  58. Painter RC, Roseboom TJ, Bleker OP (2005) Prenatal exposure to the Dutch famine and disease in later life: an overview. Reprod Toxicol 20:345–352.  https://doi.org/10.1016/j.reprotox.2005.04.005CrossRefPubMedGoogle Scholar
  59. Pallotta MM et al (2019) In vitro exposure to CPF affects bovine sperm epigenetic gene methylation pattern and the ability of sperm to support fertilization and embryo development. Environ Mol Mutagen 60:85–95.  https://doi.org/10.1002/em.22242CrossRefPubMedGoogle Scholar
  60. Pembrey ME et al (2006) Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 14:159–166.  https://doi.org/10.1038/sj.ejhg.5201538CrossRefPubMedGoogle Scholar
  61. Pessot CA et al (1989) Presence of RNA in the sperm nucleus. Biochem Biophys Res Commun 158:272–278CrossRefGoogle Scholar
  62. Reik W, Walter J (2001) Genomic imprinting: parental influence on the genome. Nat Rev Genet 2:21–32.  https://doi.org/10.1038/35047554CrossRefPubMedGoogle Scholar
  63. Rotondo JC et al (2012) Methylenetetrahydrofolate reductase gene promoter hypermethylation in semen samples of infertile couples correlates with recurrent spontaneous abortion. Hum Reprod 27:3632–3638.  https://doi.org/10.1093/humrep/des319CrossRefPubMedGoogle Scholar
  64. Santi D, De Vincentis S, Magnani E, Spaggiari G (2017) Impairment of sperm DNA methylation in male infertility: a meta-analytic study. Andrology 5:695–703.  https://doi.org/10.1111/andr.12379CrossRefPubMedGoogle Scholar
  65. Seisenberger S et al (2012) The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol Cell 48:849–862.  https://doi.org/10.1016/j.molcel.2012.11.001CrossRefPubMedPubMedCentralGoogle Scholar
  66. Sendler E et al (2013) Stability, delivery and functions of human sperm RNAs at fertilization. Nucleic Acids Res 41:4104–4117.  https://doi.org/10.1093/nar/gkt132CrossRefPubMedPubMedCentralGoogle Scholar
  67. Sharma U et al (2016) Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351:391–396.  https://doi.org/10.1126/science.aad6780CrossRefPubMedGoogle Scholar
  68. Sharma U et al (2018) Small RNAs are trafficked from the epididymis to developing mammalian sperm. Dev Cell 46:481–494.e486.  https://doi.org/10.1016/j.devcel.2018.06.023CrossRefPubMedGoogle Scholar
  69. Siddeek B, Mauduit C, Simeoni U, Benahmed M (2018) Sperm epigenome as a marker of environmental exposure and lifestyle, at the origin of diseases inheritance. Mutat Res 778:38–44.  https://doi.org/10.1016/j.mrrev.2018.09.001CrossRefPubMedGoogle Scholar
  70. Skinner MK et al (2018) Alterations in sperm DNA methylation, non-coding RNA and histone retention associate with DDT-induced epigenetic transgenerational inheritance of disease. Epigenetics Chromatin 11:8.  https://doi.org/10.1186/s13072-018-0178-0CrossRefPubMedPubMedCentralGoogle Scholar
  71. Spinelli P et al (2019) Identification of the novel Ido1 imprinted locus and its potential epigenetic role in pregnancy loss. Hum Mol Genet 28:662.  https://doi.org/10.1093/hmg/ddy383CrossRefPubMedGoogle Scholar
  72. Tian M, Liu L, Zhang J, Huang Q, Shen H (2018) Positive association of low-level environmental phthalate exposure with sperm motility was mediated by DNA methylation: a pilot study. Chemosphere 220:459–467.  https://doi.org/10.1016/j.chemosphere.2018.12.155CrossRefPubMedGoogle Scholar
  73. Waddington CH (1942) The epigenotype. Endeavour 1:18–20Google Scholar
  74. Wu SF, Zhang H, Cairns BR (2011) Genes for embryo development are packaged in blocks of multivalent chromatin in zebrafish sperm. Genome Res 21:578–589.  https://doi.org/10.1101/gr.113167.110CrossRefPubMedPubMedCentralGoogle Scholar
  75. Zhang Y et al (2018) Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs. Nat Cell Biol 20:535–540.  https://doi.org/10.1038/s41556-018-0087-2CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Andrology and IVF Laboratories, Department of Surgery, and Department of Human GeneticsUniversity of Utah School of MedicineSalt Lake CityUSA

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