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.

Understanding transgenerational epigenetic inheritance via the gametes in mammals

Key Points

  • Reprogramming of the epigenome in mammals occurs in both the germline and the early developing embryo. Some regions of the epigenome appear to escape this process.

  • Parentally imprinted genes are not reprogrammed during early development but are reprogrammed in the germline.

  • A small number of genes escape reprogramming at both stages. This includes some transgenes (that are made up of head-to-tail repeats) and some single-copy genes that are driven off repeated elements, such as retrotransposons.

  • The molecular nature of the molecules involved in this transgenerational epigenetic inheritance via the gametes is under investigation. The prevailing view has been that DNA methylation is the most likely candidate.

  • Here we suggest that RNA that is carried from the mature gametes to the zygote may be the molecule that carries this memory of transcriptional state across generations.

Abstract

It is known that information that is not contained in the DNA sequence — epigenetic information — can be inherited from the parent to the offspring. However, many questions remain unanswered regarding the extent and mechanisms of such inheritance. In this Review, we consider the evidence for transgenerational epigenetic inheritance via the gametes, including cases of environmentally induced epigenetic changes. The molecular basis of this inheritance remains unclear, but recent evidence points towards diffusible factors, in particular RNA, rather than DNA methylation or chromatin. Interestingly, many cases of epigenetic inheritance seem to involve repeat sequences.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Transgenerational epigenetic inheritance at transgenes and metastable epialleles.
Figure 2: Heat-shock-induced disruption of heterochromatin in Drosophila melanogaster.
Figure 3: Imprinting of the Rasgrf1 differentially methylated region via piRNA-directed DNA methylation.

References

  1. 1

    Peaston, A. E. & Whitelaw, E. Epigenetics and phenotypic variation in mammals. Mamm. Genome 17, 365–374 (2006).

    PubMed  PubMed Central  Google Scholar 

  2. 2

    Monk, M., Boubelik, M. & Lehnert, S. Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development 99, 371–382 (1987).

    CAS  PubMed  Google Scholar 

  3. 3

    DeChiara, T. M., Robertson, E. J. & Efstratiadis, A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64, 849–859 (1991).

    CAS  Google Scholar 

  4. 4

    Bartolomei, M. S., Webber, A. L., Brunkow, M. E. & Tilghman, S. M. Epigenetic mechanisms underlying the imprinting of the mouse H19 gene. Genes Dev. 7, 1663–1673 (1993).

    CAS  PubMed  Google Scholar 

  5. 5

    Bartolomei, M. S., Zemel, S. & Tilghman, S. M. Parental imprinting of the mouse H19 gene. Nature 351, 153–155 (1991).

    CAS  PubMed  Google Scholar 

  6. 6

    Gregg, C. et al. High-resolution analysis of parent-of-origin allelic expression in the mouse brain. Science 329, 643–648 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Gregg, C., Zhang, J., Butler, J. E., Haig, D. & Dulac, C. Sex-specific parent-of-origin allelic expression in the mouse brain. Science 329, 682–685 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Hadchouel, M., Farza, H., Simon, D., Tiollais, P. & Pourcel, C. Maternal inhibition of hepatitis B surface antigen gene expression in transgenic mice correlates with de novo methylation. Nature 329, 454–456 (1987).

    CAS  PubMed  Google Scholar 

  9. 9

    Kearns, M., Preis, J., McDonald, M., Morris, C. & Whitelaw, E. Complex patterns of inheritance of an imprinted murine transgene suggest incomplete germline erasure. Nucleic Acids Res. 28, 3301–3309 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Allen, N. D., Norris, M. L. & Surani, M. A. Epigenetic control of transgene expression and imprinting by genotype-specific modifiers. Cell 61, 853–861 (1990).

    CAS  PubMed  Google Scholar 

  11. 11

    Swain, J. L., Stewart, T. A. & Leder, P. Parental legacy determines methylation and expression of an autosomal transgene: a molecular mechanism for parental imprinting. Cell 50, 719–727 (1987).

    CAS  PubMed  Google Scholar 

  12. 12

    Sutherland, H. G. et al. Reactivation of heritably silenced gene expression in mice. Mamm. Genome 11, 347–355 (2000).

    CAS  PubMed  Google Scholar 

  13. 13

    Sapienza, C., Peterson, A. C., Rossant, J. & Balling, R. Degree of methylation of transgenes is dependent on gamete of origin. Nature 328, 251–254 (1987).

    CAS  PubMed  Google Scholar 

  14. 14

    McGowan, R., Campbell, R., Peterson, A. & Sapienza, C. Cellular mosaicism in the methylation and expression of hemizygous loci in the mouse. Genes Dev. 3, 1669–1676 (1989).

    CAS  PubMed  Google Scholar 

  15. 15

    Garrick, D., Fiering, S., Martin, D. I. & Whitelaw, E. Repeat-induced gene silencing in mammals. Nature Genet. 18, 56–59 (1998).

    CAS  PubMed  Google Scholar 

  16. 16

    Morgan, H. D., Sutherland, H. G., Martin, D. I. & Whitelaw, E. Epigenetic inheritance at the agouti locus in the mouse. Nature Genet. 23, 314–318 (1999).

    CAS  PubMed  Google Scholar 

  17. 17

    Wolff, G. L. Influence of maternal phenotype on metabolic differentiation of agouti locus mutants in the mouse. Genetics 88, 529–539 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Duhl, D. M., Vrieling, H., Miller, K. A., Wolff, G. L. & Barsh, G. S. Neomorphic agouti mutations in obese yellow mice. Nature Genet. 8, 59–65 (1994).

    CAS  PubMed  Google Scholar 

  19. 19

    Dolinoy, D. C., Weinhouse, C., Jones, T. R., Rozek, L. S. & Jirtle, R. L. Variable histone modifications at the Avy metastable epiallele. Epigenetics 5, 637–644 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Rakyan, V. K. et al. Transgenerational inheritance of epigenetic states at the murine AxinFu allele occurs after maternal and paternal transmission. Proc. Natl Acad. Sci. USA 100, 2538–2543 (2003).

    CAS  PubMed  Google Scholar 

  21. 21

    Druker, R., Bruxner, T. J., Lehrbach, N. J. & Whitelaw, E. Complex patterns of transcription at the insertion site of a retrotransposon in the mouse. Nucleic Acids Res. 32, 5800–5808 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Weinhouse, C. et al. An expression microarray approach for the identification of metastable epialleles in the mouse genome. Epigenetics 6, 1105–1113 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Rakyan, V. K., Blewitt, M. E., Druker, R., Preis, J. I. & Whitelaw, E. Metastable epialleles in mammals. Trends Genet. 18, 348–351 (2002).

    CAS  PubMed  Google Scholar 

  24. 24

    Waterland, R. A. et al. Season of conception in rural Gambia affects DNA methylation at putative human metastable epialleles. PLoS Genet. 6, e1001252 (2010). This paper was the first to identify what are thought to be metastable epialleles in humans.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Roemer, I., Reik, W., Dean, W. & Klose, J. Epigenetic inheritance in the mouse. Curr. Biol. 7, 277–280 (1997).

    CAS  PubMed  Google Scholar 

  26. 26

    Reik, W. et al. Adult phenotype in the mouse can be affected by epigenetic events in the early embryo. Development 119, 933–942 (1993).

    CAS  PubMed  Google Scholar 

  27. 27

    Wolff, G. L., Kodell, R. L., Moore, S. R. & Cooney, C. A. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 12, 949–957 (1998).

    CAS  PubMed  Google Scholar 

  28. 28

    Blewitt, M. E., Vickaryous, N. K., Paldi, A., Koseki, H. & Whitelaw, E. Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice. PLoS Genet. 2, e49 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Kaminen-Ahola, N. et al. Maternal ethanol consumption alters the epigenotype and the phenotype of offspring in a mouse model. PLoS Genet. 6, e1000811 (2010).

    PubMed  PubMed Central  Google Scholar 

  30. 30

    Waterland, R. A. & Jirtle, R. L. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol. Cell. Biol. 23, 5293–5300 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Cooney, C. A., Dave, A. A. & Wolff, G. L. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J. Nutr. 132, 2393S–2400S (2002).

    CAS  PubMed  Google Scholar 

  32. 32

    Dolinoy, D. C., Weidman, J. R., Waterland, R. A. & Jirtle, R. L. Maternal genistein alters coat colour and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ. Health Perspect. 114, 567–572 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Rakyan, V. K., Down, T. A., Balding, D. J. & Beck, S. Epigenome-wide association studies for common human diseases. Nature Rev. Genet. 12, 529–541 (2011).

    CAS  PubMed  Google Scholar 

  34. 34

    Fraga, M. F. et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl Acad. Sci. USA 102, 10604–10609 (2005).

    CAS  PubMed  Google Scholar 

  35. 35

    Oates, N. A. et al. Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly. Am. J. Hum. Genet. 79, 155–162 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Mill, J. et al. Evidence for monozygotic twin (MZ) discordance in methylation level at two CpG sites in the promoter region of the catechol-O-methyltransferase (COMT) gene. Am. J. Med. Genet. B 141, 421–425 (2006).

    Google Scholar 

  37. 37

    Baranzini, S. E. et al. Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464, 1351–1356 (2010). This is currently the most comprehensive study of the epigenome in monozygotic twins.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Kaminsky, Z. A. et al. DNA methylation profiles in monozygotic and dizygotic twins. Nature Genet. 41, 240–245 (2009).

    CAS  PubMed  Google Scholar 

  39. 39

    Francis, D. D. & Meaney, M. J. Maternal care and the development of stress responses. Curr. Opin. Neurobiol. 9, 128–134 (1999).

    CAS  PubMed  Google Scholar 

  40. 40

    Weaver, I. C. et al. Epigenetic programming by maternal behaviour. Nature Neurosci. 7, 847–854 (2004).

    CAS  PubMed  Google Scholar 

  41. 41

    Youngson, N. A. & Whitelaw, E. Transgenerational epigenetic effects. Annu. Rev. Genomics Hum. Genet. 9, 233–257 (2008).

    CAS  PubMed  Google Scholar 

  42. 42

    Anway, M. D., Cupp, A. S., Uzumcu, M. & Skinner, M. K. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308, 1466–1469 (2005).

    CAS  PubMed  Google Scholar 

  43. 43

    Guerrero-Bosagna, C., Settles, M., Lucker, B. & Skinner, M. K. Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS ONE 5, e13100 (2010).

    PubMed  PubMed Central  Google Scholar 

  44. 44

    Waterland, R. A., Travisano, M. & Tahiliani, K. G. Diet-induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female. FASEB J. 21, 3380–3385 (2007).

    CAS  PubMed  Google Scholar 

  45. 45

    Cropley, J. E., Suter, C. M., Beckman, K. B. & Martin, D. I. Germ-line epigenetic modification of the murine Avy allele by nutritional supplementation. Proc. Natl Acad. Sci. USA 103, 17308–17312 (2006).

    CAS  PubMed  Google Scholar 

  46. 46

    Cropley, J. E., Suter, C. M. & Martin, D. I. Methyl donors change the germline epigenetic state of the Avy allele. FASEB J. 21, 3021; author reply 3021–3022 (2007).

    CAS  PubMed  Google Scholar 

  47. 47

    Hales, C. N. & Barker, D. J. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35, 595–601 (1992).

    CAS  PubMed  Google Scholar 

  48. 48

    McMillen, I. C. & Robinson, J. S. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol. Rev. 85, 571–633 (2005).

    CAS  PubMed  Google Scholar 

  49. 49

    Gluckman, P. D., Hanson, M. A. & Beedle, A. S. Non-genomic transgenerational inheritance of disease risk. Bioessays 29, 145–154 (2007).

    CAS  Google Scholar 

  50. 50

    Kaati, G., Bygren, L. O. & Edvinsson, S. Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period. Eur. J. Hum. Genet. 10, 682–688 (2002).

    CAS  PubMed  Google Scholar 

  51. 51

    Lumey, L. H., Stein, A. D., Kahn, H. S. & Romijn, J. A. Lipid profiles in middle-aged men and women after famine exposure during gestation: the Dutch Hunger Winter Families Study. Am. J. Clin. Nutr. 89, 1737–1743 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Pembrey, M. E. et al. Sex-specific, male-line transgenerational responses in humans. Eur. J. Hum. Genet. 14, 159–166 (2006).

    PubMed  Google Scholar 

  53. 53

    Heijmans, B. T. et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc. Natl Acad. Sci. USA 105, 17046–17049 (2008).

    CAS  PubMed  Google Scholar 

  54. 54

    Jimenez-Chillaron, J. C. et al. Intergenerational transmission of glucose intolerance and obesity by in utero undernutrition in mice. Diabetes 58, 460–468 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Ng, S. F. et al. Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature 467, 963–966 (2010). This is a carefully executed study revealing transgenerational epigenetic inheritance of phenotype in rats. This is a clear case of inheritance of non-genetic information via the ejaculate.

    CAS  PubMed  Google Scholar 

  56. 56

    Carone, B. R. et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 1084–1096 (2010). This is another study that reveals the inheritance of epigenetic information (in this case, DNA methylation) from sire to offspring.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Lillycrop, K. A. et al. Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPARα promoter of the offspring. Br. J. Nutr. 100, 278–282 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Seong, K. H., Li, D., Shimizu, H., Nakamura, R. & Ishii, S. Inheritance of stress-induced, ATF-2-dependent epigenetic change. Cell 145, 1049–1061 (2011). This elegant study uses genetics in D. melanogaster to show that transgenerational memory of an environmental event (heat stress) can occur in trans.

    CAS  PubMed  Google Scholar 

  59. 59

    Santos, F., Hendrich, B., Reik, W. & Dean, W. Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev. Biol. 241, 172–182 (2002).

    CAS  PubMed  Google Scholar 

  60. 60

    Lane, N. et al. Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 35, 88–93 (2003).

    CAS  PubMed  Google Scholar 

  61. 61

    Hajkova, P. et al. Epigenetic reprogramming in mouse primordial germ cells. Mech. Dev. 117, 15–23 (2002).

    CAS  PubMed  Google Scholar 

  62. 62

    Hajkova, P. et al. Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature 452, 877–881 (2008).

    CAS  PubMed  Google Scholar 

  63. 63

    Popp, C. et al. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 463, 1101–1105 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Borgel, J. et al. Targets and dynamics of promoter DNA methylation during early mouse development. Nature Genet. 42, 1093–1100 (2010).

    CAS  PubMed  Google Scholar 

  65. 65

    Chan, T. L. et al. Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nature Genet. 38, 1178–1183 (2006).

    CAS  PubMed  Google Scholar 

  66. 66

    Ligtenberg, M. J. et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nature Genet. 41, 112–117 (2009).

    CAS  PubMed  Google Scholar 

  67. 67

    Suter, C. M., Martin, D. I. & Ward, R. L. Germline epimutation of MLH1 in individuals with multiple cancers. Nature Genet. 36, 497–501 (2004).

    CAS  PubMed  Google Scholar 

  68. 68

    Hitchins, M. P. et al. Inheritance of a cancer-associated MLH1 germ-line epimutation. N. Engl. J. Med. 356, 697–705 (2007).

    CAS  PubMed  Google Scholar 

  69. 69

    Chong, S., Youngson, N. A. & Whitelaw, E. Heritable germline epimutation is not the same as transgenerational epigenetic inheritance. Nature Genet. 39, 574–575; author reply 575–576 (2007).

    CAS  PubMed  Google Scholar 

  70. 70

    Suter, C. M. & Martin, D. I. Inherited epimutation or a haplotypic basis for the propensity to silence? Nature Genet. 39, 573; author reply 576 (2007).

  71. 71

    Hitchins, M. P. & Ward, R. L. Erasure of MLH1 methylation in spermatozoa—implications for epigenetic inheritance. Nature Genet. 39, 1289 (2007).

    CAS  PubMed  Google Scholar 

  72. 72

    Goel, A. et al. De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one. Int. J. Cancer 128, 869–878 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Lister, R. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315–322 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Kriaucionis, S. & Heintz, N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929–930 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Ito, S. et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333, 1300–1303 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    He, Y. F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Hammoud, S. S. et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473–478 (2009). This paper uses genome-wide methods to show that nucleosomes and histone marks retained in human sperm are enriched at loci important for development.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Brykczynska, U. et al. Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nature Struct. Mol. Biol. 17, 679–687 (2010). This study shows that promoters with distinct gene function and developmental expression patterns are selectively marked by active and repressive histone methylation in human and mouse sperm. They propose a model in which sperm-inherited nucleosomes are retained during zygotic reprogramming.

    CAS  Google Scholar 

  80. 80

    Puschendorf, M. et al. PRC1 and Suv39h specify parental asymmetry at constitutive heterochromatin in early mouse embryos. Nature Genet. 40, 411–420 (2008).

    CAS  PubMed  Google Scholar 

  81. 81

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

    CAS  PubMed  Google Scholar 

  82. 82

    Deal, R. B., Henikoff, J. G. & Henikoff, S. Genome-wide kinetics of nucleosome turnover determined by metabolic labelling of histones. Science 328, 1161–1164 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Henikoff, S. & Shilatifard, A. Histone modification: cause or cog? Trends Genet. 27, 389–396 (2011).

    CAS  PubMed  Google Scholar 

  84. 84

    Chandler, V. L. Paramutation's properties and puzzles. Science 330, 628–629 (2010).

    CAS  PubMed  Google Scholar 

  85. 85

    Arteaga-Vazquez, M. A. & Chandler, V. L. Paramutation in maize: RNA mediated trans-generational gene silencing. Curr. Opin. Genet. Dev. 20, 156–163 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Patterson, G. I., Thorpe, C. J. & Chandler, V. L. Paramutation, an allelic interaction, is associated with a stable and heritable reduction of transcription of the maize b regulatory gene. Genetics 135, 881–894 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Cavalli, G. Chromosome kissing. Curr. Opin. Genet. Dev. 17, 443–450 (2007).

    CAS  PubMed  Google Scholar 

  88. 88

    Alleman, M. et al. An RNA-dependent RNA polymerase is required for paramutation in maize. Nature 442, 295–298 (2006).

    CAS  PubMed  Google Scholar 

  89. 89

    Sidorenko, L. et al. A dominant mutation in mediator of paramutation2, one of three second-largest subunits of a plant-specific RNA polymerase, disrupts multiple siRNA silencing processes. PLoS Genet. 5, e1000725 (2009).

    PubMed  PubMed Central  Google Scholar 

  90. 90

    Stam, M. & Mittelsten Scheid, O. Paramutation: an encounter leaving a lasting impression. Trends Plant Sci. 10, 283–290 (2005).

    CAS  PubMed  Google Scholar 

  91. 91

    Chong, S. et al. Modifiers of epigenetic reprogramming show paternal effects in the mouse. Nature Genet. 39, 614–622 (2007).

    CAS  PubMed  Google Scholar 

  92. 92

    Yazbek, S. N., Spiezio, S. H., Nadeau, J. H. & Buchner, D. A. Ancestral paternal genotype controls body weight and food intake for multiple generations. Hum. Mol. Genet. 19, 4134–4144 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Krawetz, S. A. Paternal contribution: new insights and future challenges. Nature Rev. Genet. 6, 633–642 (2005).

    CAS  PubMed  Google Scholar 

  94. 94

    Zhao, Y. et al. Characterization and quantification of mRNA transcripts in ejaculated spermatozoa of fertile men by serial analysis of gene expression. Hum. Reprod. 21, 1583–1590 (2006).

    CAS  PubMed  Google Scholar 

  95. 95

    Watanabe, T. et al. Identification and characterization of two novel classes of small RNAs in the mouse germline: retrotransposon-derived siRNAs in oocytes and germline small RNAs in testes. Genes Dev. 20, 1732–1743 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Watanabe, T. et al. Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453, 539–543 (2008).

    CAS  PubMed  Google Scholar 

  97. 97

    Tam, O. H. et al. Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 453, 534–538 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Melnyk, C. W., Molnar, A. & Baulcombe, D. C. Intercellular and systemic movement of RNA silencing signals. EMBO J. 30, 3553–3563 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Slotkin, R. K. et al. Epigenetic reprogramming and small RNA silencing of transposable elements in pollen. Cell 136, 461–472 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Murchison, E. P. et al. Critical roles for Dicer in the female germline. Genes Dev. 21, 682–693 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Saito, K. & Siomi, M. C. Small RNA-mediated quiescence of transposable elements in animals. Dev. Cell 19, 687–697 (2010).

    CAS  PubMed  Google Scholar 

  102. 102

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

    CAS  PubMed  Google Scholar 

  103. 103

    Gan, H. et al. piRNA profiling during specific stages of mouse spermatogenesis. RNA 17, 1191–1203 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Watanabe, T. et al. Role for piRNAs and noncoding RNA in de novo DNA methylation of the imprinted mouse Rasgrf1 locus. Science 332, 848–852 (2011). This study reveals a role for piRNAs in directing DNA methylation at the imprinted Rasgrf1 locus in the mouse.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Bucheton, A., Paro, R., Sang, H. M., Pelisson, A. & Finnegan, D. J. The molecular basis of I-R. hybrid dysgenesis in Drosophila melanogaster: identification, cloning, and properties of the I factor. Cell 38, 153–163 (1984).

    CAS  PubMed  Google Scholar 

  106. 106

    Bregliano, J. C. et al. Hybrid dysgenesis in Drosophila melanogaster. Science 207, 606–611 (1980).

    CAS  PubMed  Google Scholar 

  107. 107

    Brennecke, J. et al. An epigenetic role for maternally inherited piRNAs in transposon silencing. Science 322, 1387–1392 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Hwang, H. W., Wentzel, E. A. & Mendell, J. T. A hexanucleotide element directs microRNA nuclear import. Science 315, 97–100 (2007).

    CAS  Google Scholar 

  109. 109

    Taft, R. J. et al. Nuclear-localized tiny RNAs are associated with transcription initiation and splice sites in metazoans. Nature Struct. Mol. Biol. 17, 1030–1034 (2010).

    CAS  Google Scholar 

  110. 110

    Rassoulzadegan, M. et al. RNA-mediated non-Mendelian inheritance of an epigenetic change in the mouse. Nature 441, 469–474 (2006).

    CAS  PubMed  Google Scholar 

  111. 111

    Lewis, B. P., Shih, I. H., Jones-Rhoades, M. W., Bartel, D. P. & Burge, C. B. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Wagner, K. D. et al. RNA induction and inheritance of epigenetic cardiac hypertrophy in the mouse. Dev. Cell 14, 962–969 (2008).

    CAS  PubMed  Google Scholar 

  113. 113

    Grandjean, V. et al. The miR-124–Sox9 paramutation: RNA-mediated epigenetic control of embryonic and adult growth. Development 136, 3647–3655 (2009).

    CAS  PubMed  Google Scholar 

  114. 114

    Katz, D. J., Edwards, T. M., Reinke, V. & Kelly, W. G. A C. elegans LSD1 demethylase contributes to germline immortality by reprogramming epigenetic memory. Cell 137, 308–320 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Metivier, R. et al. Cyclical DNA methylation of a transcriptionally active promoter. Nature 452, 45–50 (2008).

    CAS  Google Scholar 

  116. 116

    Kangaspeska, S. et al. Transient cyclical methylation of promoter DNA. Nature 452, 112–115 (2008).

    CAS  Google Scholar 

  117. 117

    Scharf, A. N., Barth, T. K. & Imhof, A. Establishment of histone modifications after chromatin assembly. Nucleic Acids Res. 37, 5032–5040 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Yisraeli, J., Frank, D., Razin, A. & Cedar, H. Effect of in vitro DNA methylation on beta-globin gene expression. Proc. Natl Acad. Sci. USA 85, 4638–4642 (1988).

    CAS  PubMed  Google Scholar 

  119. 119

    Montero, L. M. et al. The distribution of 5-methylcytosine in the nuclear genome of plants. Nucleic Acids Res. 20, 3207–3210 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Ehrlich, M. et al. Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells. Nucleic Acids Res. 10, 2709–2721 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Antequera, F., Tamame, M., Villanueva, J. R. & Santos, T. DNA methylation in the fungi. J. Biol. Chem. 259, 8033–8036 (1984).

    CAS  PubMed  Google Scholar 

  122. 122

    Lyko, F. et al. The honey bee epigenomes: differential methylation of brain DNA in queens and workers. PLoS Biol. 8, e1000506 (2010).

    PubMed  PubMed Central  Google Scholar 

  123. 123

    Lyko, F., Ramsahoye, B. H. & Jaenisch, R. DNA methylation in Drosophila melanogaster. Nature 408, 538–540 (2000).

    CAS  PubMed  Google Scholar 

  124. 124

    Bird, A. P., Taggart, M. H., Nicholls, R. D. & Higgs, D. R. Non-methylated CpG-rich islands at the human alpha-globin locus: implications for evolution of the α-globin pseudogene. EMBO J. 6, 999–1004 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Smallwood, S. A. et al. Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Nature Genet. 43, 811–814 (2011).

    CAS  PubMed  Google Scholar 

  126. 126

    Kouzminova, E. & Selker, E. U. dim-2 encodes a DNA methyltransferase responsible for all known cytosine methylation in Neurospora. EMBO J. 20, 4309–4323 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Tamaru, H. & Selker, E. U. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414, 277–283 (2001).

    CAS  PubMed  Google Scholar 

  128. 128

    Weber, M. et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nature Genet. 37, 853–862 (2005).

    CAS  PubMed  Google Scholar 

  129. 129

    Henikoff, S. Position-effect variegation after 60 years. Trends Genet. 6, 422–426 (1990).

    CAS  PubMed  Google Scholar 

  130. 130

    Ebert, A., Lein, S., Schotta, G. & Reuter, G. Histone modification and the control of heterochromatic gene silencing in Drosophila. Chromosome Res. 14, 377–392 (2006).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

E.W. is a National Health and Medical Research Council (NHMRC) Australia Fellow. We thank N. Youngson for helpful discussions and M. Blewitt for critical reading of the manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Emma Whitelaw.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Glossary

Heterochromatin

The portion of the genome that stays highly condensed throughout the cell cycle. It contains a high proportion of repetitive sequences, is gene-poor overall and is enriched for histone marks, such as histone H3 lysine 9 trimethylation (H3K9me3) and H4K20me3, as well as DNA methylation. Heterochromatin is generally associated with gene silencing.

Histone modifications

Covalent alterations of histone tail residues that can alter chromatin structure. Modifications include phosphorylation, methylation, acetylation, sumoylation and ubiquitylation.

Intracisternal A particle

(IAP). A long terminal repeat (LTR)-containing retrotransposon of mice that resembles a retrovirus but has a defective env gene.

Genistein

An isoflavone found in plants that acts as an antioxidant and binds to the oestrogen receptor, hence its classification as a phytoestrogen.

Hypothalamic–pituitary–adrenal axis

(HPA axis). A set of interactions between the hypothalamus, the pituitary gland and the adrenal glands that control reactions to stress.

Glucocorticoid receptor

The receptor to which cortisol and other glucocorticoids bind. It is expressed throughout the body and controls transcription of many genes involved in development, metabolism and the immune response.

Hippocampus

A neurogenic region of the forebrain that has important functions in learning and memory.

Vinclozolin

A fungicide used on vines, fruits and vegetables. It is associated with the development of testicular tumours. There is some evidence that it is carcinogenic and can act as an endrocrine disruptor.

Peroxisome proliferator-activated receptor alpha

(PPARα). A nuclear receptor and transcription factor involved in lipid metabolism.

Bisulphite sequencing

Treatment of DNA with sulphite ions increases the relative resistance of the conversion of methylcytosine to uracil compared with cytosine. PCR amplification and sequencing of the DNA following conversion shows a thymine where a cytosine was located, whereas persistence of a cytosine reflects its methylation in the starting DNA sample.

Epimutations

Mitotically heritable changes in epigenetic state but not gene sequence. Epimutation usually takes place by an abnormal increase or decrease in the methylation status of a gene. The heritability of epimutations across generations is currently under debate.

MLH1

MutL homologue 1, colon cancer nonpolyposis type 2 (Escherichia coli) is a human gene coding for a protein that has an important role in DNA repair.

MSH2

MutS homologue 2, colon cancer nonpolyposis type 2 (Escherichia coli) is another human gene coding for a protein involved in DNA repair.

Polycomb repressive complex 1

(PRC1). Silencing of the homeotic genes in development requires the Polycomb group proteins (PcGs). PcGs form two distinct multiprotein complexes, PRC1 and PRC2.

MicroRNAs

(miRNAs). Evolutionarily conserved small non-coding RNAs (~22-nucleotides long) that silence gene expression by degrading or inhibiting translation of mRNA transcripts in a sequence-specific manner.

Endogenous small interfering RNAs

(endo-siRNAs). Small RNAs that originate, in a Dicer-dependent manner, from long double-stranded (sense–antisense or hairpin) precursors. Initially mainly thought of as a mechanism of host defence against exogenous double-stranded RNA, endo-siRNAs are now known to also regulate endogenous mRNAs in mouse oocytes and Caenorhabditis elegans.

PIWI-interacting RNAs

(piRNAs). Small (24–31 bp) RNAs that are associated with PIWI-clade proteins of the Argonaute family. They ensure genome stability in the germline of flies, mice and zebrafish by silencing transposable and repetitive elements.

Position effect variegation

(PEV). This term describes a type of phenotypic variegation among cells of the same type that is the result of mosaic silencing of a particular gene. The variegation in these cases is due to the position of the gene adjacent to a heterochromatic region of the chromosome.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Daxinger, L., Whitelaw, E. Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat Rev Genet 13, 153–162 (2012). https://doi.org/10.1038/nrg3188

Download citation

Further reading

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