Review Article | Published:

Functions and mechanisms of epigenetic inheritance in animals

Nature Reviews Molecular Cell Biologyvolume 19pages774790 (2018) | Download Citation


The idea that epigenetic determinants such as DNA methylation, histone modifications or RNA can be passed to the next generation through meiotic products (gametes) is long standing. Such meiotic epigenetic inheritance (MEI) is fairly common in yeast, plants and nematodes, but its extent in mammals has been much debated. Advances in genomics techniques are now driving the profiling of germline and zygotic epigenomes, thereby improving our understanding of MEI in diverse species. Whereas the role of DNA methylation in MEI remains unclear, insights from genome-wide studies suggest that a previously underappreciated fraction of mammalian genomes bypass epigenetic reprogramming during development. Notably, intergenerational inheritance of histone modifications, tRNA fragments and microRNAs can affect gene regulation in the offspring. It is important to note that MEI in mammals rarely constitutes transgenerational epigenetic inheritance (TEI), which spans multiple generations. In this Review, we discuss the examples of MEI in mammals, including mammalian epigenome reprogramming, and the molecular mechanisms of MEI in vertebrates in general. We also discuss the implications of the inheritance of histone modifications and small RNA for embryogenesis in metazoans, with a particular focus on insights gained from genome-wide studies.

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  1. 1.

    Richards, E. J. Inherited epigenetic variation — revisiting soft inheritance. Nat. Rev. Genet. 7, 395–401 (2006).

  2. 2.

    Daxinger, L. & Whitelaw, E. Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat. Rev. Genet. 13, 153–162 (2012).

  3. 3.

    Miska, E. A. & Ferguson-Smith, A. C. Transgenerational inheritance: models and mechanisms of non-DNA sequence-based inheritance. Science 354, 59–63 (2016).

  4. 4.

    Greally, J. M. A user’s guide to the ambiguous word ‘epigenetics’. Nat. Rev. Mol. Cell Biol. 19, 207–208 (2018).

  5. 5.

    Adams, F. The Genuine Works of Hippocrates (William Wood, NY, USA, 1891).

  6. 6.

    Lamarck, J. B. Philosophie Zoologique (JB Baillière, Paris, 1809).

  7. 7.

    Waddington, C. H. Genetic assimilation of an acquired character. Int. J. Org. Evol. 7, 118–126 (1953).

  8. 8.

    Waddington, C. H. Genetic assimilation of the bithorax phenotype. Evolution 10, 1 (1956).

  9. 9.

    Rutherford, S. L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998). This work describes the key role of Hsp90 in the buffering of naturally occurring phenotypic variation in fruit flies.

  10. 10.

    Zhao, C. Q., Young, M. R., Diwan, B. A., Coogan, T. P. & Waalkes, M. P. Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc. Natl Acad. Sci. USA 94, 10907–10912 (1997).

  11. 11.

    James, S. J. et al. Mechanisms of DNA damage, DNA hypomethylation, and tumor progression in the folate/methyl-deficient rat model of hepatocarcinogenesis. J. Nutr. 133, 3740S–3747S (2003).

  12. 12.

    Baccarelli, A. & Bollati, V. Epigenetics and environmental chemicals. Curr. Opin. Pediatr. 21, 243–251 (2009).

  13. 13.

    Blaschke, K. et al. Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature 500, 222–226 (2013).

  14. 14.

    Vickers, M. H. Early life nutrition, epigenetics and programming of later life disease. Nutrients 6, 2165–2178 (2014).

  15. 15.

    Klengel, T. & Binder, E. B. Epigenetics of stress-related psychiatric disorders and gene x environment interactions. Neuron 86, 1343–1357 (2015).

  16. 16.

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

  17. 17.

    Dunn, G. A. & Bale, T. L. Maternal high-fat diet effects on third-generation female body size via the paternal lineage. Endocrinology 152, 2228–2236 (2011).

  18. 18.

    Crews, D. et al. Epigenetic transgenerational inheritance of altered stress responses. Proc. Natl Acad. Sci. USA 109, 9143–9148 (2012).

  19. 19.

    Padmanabhan, N. et al. Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 155, 81–93 (2013).

  20. 20.

    Gapp, K. et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat. Neurosci. 17, 667–669 (2014).

  21. 21.

    Rodgers, A. B., Morgan, C. P., Leu, N. A. & Bale, T. L. Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc. Natl Acad. Sci. USA 112, 13699–13704 (2015).

  22. 22.

    Rusche, L. N., Kirchmaier, A. L. & Rine, J. The establishment, inheritance, and function of silenced chromatin in Saccharomyces cerevisiae. Annu. Rev. Biochem. 72, 481–516 (2003).

  23. 23.

    Casadesus, J. & Low, D. Epigenetic gene regulation in the bacterial world. Microbiol. Mol. Biol. Rev. 70, 830–856 (2006).

  24. 24.

    Quadrana, L. & Colot, V. Plant transgenerational epigenetics. Annu. Rev. Genet. 50, 467–491 (2016).

  25. 25.

    Hollick, J. B. Paramutation and related phenomena in diverse species. Nat. Rev. Genet. 18, 5–23 (2017).

  26. 26.

    Houri-Zeevi, L. & Rechavi, O. A. Matter of time: small RNAs regulate the duration of epigenetic inheritance. Trends Genet. 33, 46–57 (2017).

  27. 27.

    Minkina, O. & Hunter, C. P. Intergenerational transmission of gene regulatory information in Caenorhabditis elegans. Trends Genet. 34, 54–64 (2017).

  28. 28.

    Serobyan, V. & Sommer, R. J. Developmental systems of plasticity and trans-generational epigenetic inheritance in nematodes. Curr. Opin. Genet. Dev. 45, 51–57 (2017).

  29. 29.

    Springer, N. M. & Schmitz, R. J. Exploiting induced and natural epigenetic variation for crop improvement. Nat. Rev. Genet. 18, 563–575 (2017).

  30. 30.

    Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).

  31. 31.

    Bernstein, E., Caudy, A. A., Hammond, S. M. & Hannon, G. J. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409, 363–366 (2001).

  32. 32.

    Ketting, R. F. et al. Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev. 15, 2654–2659 (2001).

  33. 33.

    Yigit, E. et al. Analysis of the C. elegans Argonaute family reveals that distinct Argonautes act sequentially during RNAi. Cell 127, 747–757 (2006).

  34. 34.

    Sijen, T. et al. On the role of RNA amplification in dsRNA-triggered gene silencing. Cell 107, 465–476 (2001).

  35. 35.

    Pak, J. & Fire, A. Distinct populations of primary and secondary effectors during RNAi in C. elegans. Science 315, 241–244 (2007).

  36. 36.

    Swarts, D. C. et al. The evolutionary journey of Argonaute proteins. Nat. Struct. Mol. Biol. 21, 743–753 (2014).

  37. 37.

    Guang, S. et al. An Argonaute transports siRNAs from the cytoplasm to the nucleus. Science 321, 537–541 (2008).

  38. 38.

    Rechavi, O., Minevich, G. & Hobert, O. Transgenerational inheritance of an acquired small RNA-based antiviral response in C. elegans. Cell 147, 1248–1256 (2011).

  39. 39.

    Burton, N. O., Burkhart, K. B. & Kennedy, S. Nuclear RNAi maintains heritable gene silencing in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 108, 19683–19688 (2011).

  40. 40.

    Ishidate, T. et al. ZNFX-1 functions within perinuclear nuage to balance epigenetic signals. Mol. Cell 70, 639–649 (2018).

  41. 41.

    Wan, G. et al. Spatiotemporal regulation of liquid-like condensates in epigenetic inheritance. Nature 557, 679–683 (2018).

  42. 42.

    Bagijn, M. P. et al. Function, targets, and evolution of Caenorhabditis elegans piRNAs. Science 337, 574–578 (2012).

  43. 43.

    Lee, H. C. et al. C. elegans piRNAs mediate the genome-wide surveillance of germline transcripts. Cell 150, 78–87 (2012).

  44. 44.

    Ashe, A. et al. piRNAs can trigger a multigenerational epigenetic memory in the germline of C. elegans. Cell 150, 88–99 (2012).

  45. 45.

    Luteijn, M. J. et al. Extremely stable Piwi-induced gene silencing in Caenorhabditis elegans. EMBO J. 31, 3422–3430 (2012).

  46. 46.

    Shirayama, M. et al. piRNAs initiate an epigenetic memory of nonself RNA in the C. elegans germline. Cell 150, 65–77 (2012). References 44–46 describe how piRNAs contribute to transgenerational epigenetic memory in Caenorhabditis elegans.

  47. 47.

    Grishok, A., Tabara, H. & Mello, C. C. Genetic requirements for inheritance of RNAi in C. elegans. Science 287, 2494–2497 (2000).

  48. 48.

    Vastenhouw, N. L. et al. Gene expression: long-term gene silencing by RNAi. Nature 442, 882 (2006).

  49. 49.

    Kalinava, N., Ni, J. Z., Peterman, K., Chen, E. & Gu, S. G. Decoupling the downstream effects of germline nuclear RNAi reveals that H3K9me3 is dispensable for heritable RNAi and the maintenance of endogenous siRNA-mediated transcriptional silencing in Caenorhabditis elegans. Epigenetics Chromatin 10, 6 (2017).

  50. 50.

    Lev, I. et al. MET-2-dependent H3K9 methylation suppresses transgenerational small RNA inheritance. Curr. Biol. 27, 1138–1147 (2017). This work demonstrates how induction of RNAi in nematodes deficient in the H3K9 methyltransferase MET-2 results in permanent RNA responses that persist even after 30 generations.

  51. 51.

    Greer, E. L. et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479, 365–371 (2011).

  52. 52.

    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).

  53. 53.

    Gaydos, L. J., Wang, W. & Strome, S. Gene repression. H3K27me and PRC2 transmit a memory of repression across generations and during development. Science 345, 1515–1518 (2014).

  54. 54.

    Klosin, A., Casas, E., Hidalgo-Carcedo, C., Vavouri, T. & Lehner, B. Transgenerational transmission of environmental information in C. elegans. Science 356, 320–323 (2017). This report demonstrates H3K9me3-associated, temperature-induced changes in gene expression, which are heritable for at least 14 generations in the nematode Caenorhabditis elegans.

  55. 55.

    Lev, I., Gingold, H. & Rechavi, O. H3K9me3 is required for transgenerational inheritance of small RNAs that target a unique subset of newly evolved genes. bioRxiv (2018).

  56. 56.

    Lee, H. J., Hore, T. A. & Reik, W. Reprogramming the methylome: erasing memory and creating diversity. Cell Stem Cell 14, 710–719 (2014).

  57. 57.

    Eckersley-Maslin, M. A., Alda-Catalinas, C. & Reik, W. Dynamics of the epigenetic landscape during the maternal-to-zygotic transition. Nat. Rev. Mol. Cell Biol. 19, 436–450 (2018).

  58. 58.

    Ferguson-Smith, A. C. Genomic imprinting: the emergence of an epigenetic paradigm. Nat. Rev. Genet. 12, 565–575 (2011).

  59. 59.

    Reik, W., Collick, A., Norris, M. L., Barton, S. C. & Surani, M. A. Genomic imprinting determines methylation of parental alleles in transgenic mice. Nature 328, 248–251 (1987).

  60. 60.

    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).

  61. 61.

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

  62. 62.

    Bourc’his, D., Xu, G. L., Lin, C. S., Bollman, B. & Bestor, T. H. Dnmt3L and the establishment of maternal genomic imprints. Science 294, 2536–2539 (2001).

  63. 63.

    Coan, P. M., Burton, G. J. & Ferguson-Smith, A. C. Imprinted genes in the placenta — a review. Placenta 26, S10–S20 (2005).

  64. 64.

    Frost, J. M. & Moore, G. E. The importance of imprinting in the human placenta. PLOS Genet. 6, e1001015 (2010).

  65. 65.

    Nicholls, R. D. & Knepper, J. L. Genome organization, function, and imprinting in Prader–Willi and Angelman syndromes. Annu. Rev. Genom. Hum. Genet. 2, 153–175 (2001).

  66. 66.

    Inoue, A., Jiang, L., Lu, F., Suzuki, T. & Zhang, Y. Maternal H3K27me3 controls DNA methylation-independent imprinting. Nature 547, 419–424 (2017). This work demonstrates the existence of H3K27me3-dependent imprinting independently of DNA methylation during mammalian embryogenesis.

  67. 67.

    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).

  68. 68.

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

  69. 69.

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

  70. 70.

    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).

  71. 71.

    Xu, Q. & Xie, W. Epigenome in early mammalian development: inheritance, reprogramming and establishment. Trends Cell Biol. 28, 237–253 (2018).

  72. 72.

    Hitchins, M. P. Constitutional epimutation as a mechanism for cancer causality and heritability? Nat. Rev. Cancer 15, 625–634 (2015).

  73. 73.

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

  74. 74.

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

  75. 75.

    Lynch, H. T. et al. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin. Genet. 76, 1–18 (2009).

  76. 76.

    Morak, M. et al. Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC. Eur. J. Hum. Genet. 16, 804–811 (2008).

  77. 77.

    Crepin, M. et al. Evidence of constitutional MLH1 epimutation associated to transgenerational inheritance of cancer susceptibility. Hum. Mutat. 33, 180–188 (2012).

  78. 78.

    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).

  79. 79.

    Roseboom, T., de Rooij, S. & Painter, R. The Dutch famine and its long-term consequences for adult health. Early Hum. Dev. 82, 485–491 (2006).

  80. 80.

    Bygren, L. O. et al. Change in paternal grandmothers’ early food supply influenced cardiovascular mortality of the female grandchildren. BMC Genet. 15, 12 (2014).

  81. 81.

    Yehuda, R. et al. Holocaust exposure induced intergenerational effects on FKBP5 methylation. Biol. Psychiatry 80, 372–380 (2016).

  82. 82.

    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).

  83. 83.

    Painter, R. C. et al. Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life. BJOG 115, 1243–1249 (2008).

  84. 84.

    Lappalainen, T. & Greally, J. M. Associating cellular epigenetic models with human phenotypes. Nat. Rev. Genet. 18, 441–451 (2017).

  85. 85.

    Coleman, R. T. & Struhl, G. Causal role for inheritance of H3K27me3 in maintaining the OFF state of a Drosophila HOX gene. Science 356, eaai8236 (2017).

  86. 86.

    Laprell, F., Finkl, K. & Muller, J. Propagation of Polycomb-repressed chromatin requires sequence-specific recruitment to DNA. Science 356, 85–88 (2017).

  87. 87.

    Wang, X. & Moazed, D. DNA sequence-dependent epigenetic inheritance of gene silencing and histone H3K9 methylation. Science 356, 88–91 (2017).

  88. 88.

    Bohacek, J. & Mansuy, I. M. A guide to designing germline-dependent epigenetic inheritance experiments in mammals. Nat. Methods 14, 243–249 (2017).

  89. 89.

    Bestor, T. H. The DNA methyltransferases of mammals. Hum. Mol. Genet. 9, 2395–2402 (2000).

  90. 90.

    Jurkowska, R. Z., Jurkowski, T. P. & Jeltsch, A. Structure and function of mammalian DNA methyltransferases. Chembiochem 12, 206–222 (2011).

  91. 91.

    Suzuki, M. M. & Bird, A. DNA methylation landscapes: provocative insights from epigenomics. Nat. Rev. Genet. 9, 465–476 (2008).

  92. 92.

    Schubeler, D. Function and information content of DNA methylation. Nature 517, 321–326 (2015).

  93. 93.

    Simpson, V. J., Johnson, T. E. & Hammen, R. F. Caenorhabditis elegans DNA does not contain 5-methylcytosine at any time during development or aging. Nucleic Acids Res. 14, 6711–6719 (1986).

  94. 94.

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

  95. 95.

    Mayer, W., Niveleau, A., Walter, J., Fundele, R. & Haaf, T. Demethylation of the zygotic paternal genome. Nature 403, 501–502 (2000).

  96. 96.

    Oswald, J. et al. Active demethylation of the paternal genome in the mouse zygote. Curr. Biol. 10, 475–478 (2000).

  97. 97.

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

  98. 98.

    Smith, Z. D. et al. A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature 484, 339–344 (2012).

  99. 99.

    Wossidlo, M. et al. 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat. Commun. 2, 241 (2011).

  100. 100.

    Wang, L. et al. Programming and inheritance of parental DNA methylomes in mammals. Cell 157, 979–991 (2014).

  101. 101.

    Amouroux, R. et al. De novo DNA methylation drives 5hmC accumulation in mouse zygotes. Nat. Cell Biol. 18, 225–233 (2016).

  102. 102.

    Morgan, H. D., Santos, F., Green, K., Dean, W. & Reik, W. Epigenetic reprogramming in mammals. Hum. Mol. Genet. 1, R47–R58 (2005).

  103. 103.

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

  104. 104.

    Guo, H. et al. The DNA methylation landscape of human early embryos. Nature 511, 606–610 (2014).

  105. 105.

    Smith, Z. D. et al. DNA methylation dynamics of the human preimplantation embryo. Nature 511, 611–615 (2014).

  106. 106.

    Birnbaum, R. Y. et al. Coding exons function as tissue-specific enhancers of nearby genes. Genome Res. 22, 1059–1068 (2012).

  107. 107.

    Blattler, A. et al. Global loss of DNA methylation uncovers intronic enhancers in genes showing expression changes. Genome Biol. 15, 469 (2014).

  108. 108.

    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).

  109. 109.

    Guibert, S., Forne, T. & Weber, M. Global profiling of DNA methylation erasure in mouse primordial germ cells. Genome Res. 22, 633–641 (2012).

  110. 110.

    Hackett, J. A. et al. Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science 339, 448–452 (2013).

  111. 111.

    Hill, P. W. S. et al. Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte. Nature 555, 392–396 (2018).

  112. 112.

    Seisenberger, S. et al. The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol. Cell 48, 849–862 (2012).

  113. 113.

    Gkountela, S. et al. DNA demethylation dynamics in the human prenatal germline. Cell 161, 1425–1436 (2015).

  114. 114.

    Guo, F. et al. The transcriptome and DNA methylome landscapes of human primordial germ cells. Cell 161, 1437–1452 (2015).

  115. 115.

    Tang, W. W. et al. A unique gene regulatory network resets the human germline epigenome for development. Cell 161, 1453–1467 (2015).

  116. 116.

    Radford, E. J. et al. In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345, 1255903 (2014).

  117. 117.

    Hammoud, S. S. et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473–478 (2009).

  118. 118.

    Brykczynska, U. et al. Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nat. Struct. Mol. Biol. 17, 679–687 (2010).

  119. 119.

    Erkek, S. et al. Molecular determinants of nucleosome retention at CpG-rich sequences in mouse spermatozoa. Nat. Struct. Mol. Biol. 20, 868–875 (2013). References 117–119 describe potentially heritable DNA and histone modifications in the mammalian sperm.

  120. 120.

    Dahl, J. A. et al. Broad histone H3K4me3 domains in mouse oocytes modulate maternal-to-zygotic transition. Nature 537, 548–552 (2016).

  121. 121.

    Zhang, B. et al. Allelic reprogramming of the histone modification H3K4me3 in early mammalian development. Nature 537, 553–557 (2016). References 120 and 121 describe the intergenerational inheritance of the histone modification H3K4me3 in mammals and its roles during early mammalian embryogenesis.

  122. 122.

    Zheng, H. et al. Resetting epigenetic memory by reprogramming of histone modifications in mammals. Mol. Cell 63, 1066–1079 (2016).

  123. 123.

    Macleod, D., Clark, V. H. & Bird, A. Absence of genome-wide changes in DNA methylation during development of the zebrafish. Nat. Genet. 23, 139–140 (1999).

  124. 124.

    Veenstra, G. J. & Wolffe, A. P. Constitutive genomic methylation during embryonic development of Xenopus. Biochim. Biophys. Acta 1521, 39–44 (2001).

  125. 125.

    Bogdanovic, O. et al. Temporal uncoupling of the DNA methylome and transcriptional repression during embryogenesis. Genome Res. 21, 1313–1327 (2011).

  126. 126.

    Jiang, L. et al. Sperm, but not oocyte, DNA methylome is inherited by zebrafish early embryos. Cell 153, 773–784 (2013).

  127. 127.

    Potok, M. E., Nix, D. A., Parnell, T. J. & Cairns, B. R. Reprogramming the maternal zebrafish genome after fertilization to match the paternal methylation pattern. Cell 153, 759–772 (2013).

  128. 128.

    Murphy, P. J., Wu, S. F., James, C. R., Wike, C. L. & Cairns, B. R. Placeholder nucleosomes underlie germline-to-embryo DNA methylation reprogramming. Cell 172, 993–1006 (2018). This work describes placeholder nucleosomes, marked by H3K4me1 and H2AZ, which have a role in intergenerational inheritance of paternal epigenetic modifications in zebrafish.

  129. 129.

    Almeida, R. D. et al. 5-Hydroxymethyl-cytosine enrichment of non-committed cells is not a universal feature of vertebrate development. Epigenetics 7, 383–389 (2012).

  130. 130.

    Bogdanovic, O. et al. Active DNA demethylation at enhancers during the vertebrate phylotypic period. Nat. Genet. 48, 417–426 (2016).

  131. 131.

    Kamstra, J. H., Sales, L. B., Alestrom, P. & Legler, J. Differential DNA methylation at conserved non-genic elements and evidence for transgenerational inheritance following developmental exposure to mono(2-ethylhexyl) phthalate and 5-azacytidine in zebrafish. Epigenetics 10, 20 (2017).

  132. 132.

    Stadler, M. B. et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480, 490–495 (2011).

  133. 133.

    Thurman, R. E. et al. The accessible chromatin landscape of the human genome. Nature 489, 75–82 (2012).

  134. 134.

    Cavalli, G. & Paro, R. The Drosophila Fab-7 chromosomal element conveys epigenetic inheritance during mitosis and meiosis. Cell 93, 505–518 (1998).

  135. 135.

    Cavalli, G. & Paro, R. Epigenetic inheritance of active chromatin after removal of the main transactivator. Science 286, 955–958 (1999).

  136. 136.

    Ciabrelli, F. et al. Stable polycomb-dependent transgenerational inheritance of chromatin states in Drosophila. Nat. Genet. 49, 876–886 (2017). This work demonstrates how nuclear organization and Polycomb group proteins contribute to the formation of stable and transgenerationally heritable epialleles in fruit flies.

  137. 137.

    Zenk, F. et al. Germ line-inherited H3K27me3 restricts enhancer function during maternal-to-zygotic transition. Science 357, 212–216 (2017). This study reports regulation of enhancer activity at the onset of zygotic genome activation through maternally-inherited H3K27me3 in fruit fly embryos.

  138. 138.

    Wu, S. F., Zhang, H. & Cairns, B. R. Genes for embryo development are packaged in blocks of multivalent chromatin in zebrafish sperm. Genome Res. 21, 578–589 (2011).

  139. 139.

    Teperek, M. et al. Sperm is epigenetically programmed to regulate gene transcription in embryos. Genome Res. 26, 1034–1046 (2016).

  140. 140.

    Lindeman, L. C. et al. Prepatterning of developmental gene expression by modified histones before zygotic genome activation. Dev. Cell 21, 993–1004 (2011).

  141. 141.

    Akkers, R. C. et al. A hierarchy of H3K4me3 and H3K27me3 acquisition in spatial gene regulation in Xenopus embryos. Dev. Cell 17, 425–434 (2009).

  142. 142.

    Vastenhouw, N. L. et al. Chromatin signature of embryonic pluripotency is established during genome activation. Nature 464, 922–926 (2010).

  143. 143.

    Hontelez, S. et al. Embryonic transcription is controlled by maternally defined chromatin state. Nat. Commun. 6, 10148 (2015).

  144. 144.

    Balhorn, R. The protamine family of sperm nuclear proteins. Genome Biol. 8, 227 (2007).

  145. 145.

    van de Werken, C. et al. Paternal heterochromatin formation in human embryos is H3K9/HP1 directed and primed by sperm-derived histone modifications. Nat. Commun. 5, 5868 (2014).

  146. 146.

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

  147. 147.

    Brind’Amour, J. et al. An ultra-low-input native ChIP-seq protocol for genome-wide profiling of rare cell populations. Nat. Commun. 6, 6033 (2015).

  148. 148.

    Rotem, A. et al. Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state. Nat. Biotechnol. 33, 1165–1172 (2015).

  149. 149.

    Clark, S. J., Lee, H. J., Smallwood, S. A., Kelsey, G. & Reik, W. Single-cell epigenomics: powerful new methods for understanding gene regulation and cell identity. Genome Biol. 17, 72 (2016).

  150. 150.

    Siklenka, K. et al. Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science 350, aab2006 (2015). This work demonstrates how overexpression of the H3K4 methylase LSD1 during mouse spermatogenesis results in transgenerationally heritable developmental phenotypes.

  151. 151.

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

  152. 152.

    de Vanssay, A. et al. Paramutation in Drosophila linked to emergence of a piRNA-producing locus. Nature 490, 112–115 (2012).

  153. 153.

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

  154. 154.

    Chen, Q. et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351, 397–400 (2016).

  155. 155.

    Cropley, J. E. et al. Male-lineage transmission of an acquired metabolic phenotype induced by grand-paternal obesity. Mol. Metab. 5, 699–708 (2016).

  156. 156.

    Sharma, U. et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351, 391–396 (2016). References 154–156 demonstrate the importance of small RNAs in the intergenerational transmission of metabolic phenotypes in mice.

  157. 157.

    Liu, W. M. et al. Sperm-borne microRNA-34c is required for the first cleavage division in mouse. Proc. Natl Acad. Sci. USA 109, 490–494 (2012).

  158. 158.

    Yang, Q. et al. Highly sensitive sequencing reveals dynamic modifications and activities of small RNAs in mouse oocytes and early embryos. Sci. Adv. 2, e1501482 (2016).

  159. 159.

    Rechavi, O. et al. Starvation-induced transgenerational inheritance of small RNAs in C. elegans. Cell 158, 277–287 (2014).

  160. 160.

    Schott, D., Yanai, I. & Hunter, C. P. Natural RNA interference directs a heritable response to the environment. Sci. Rep. 4, 7387 (2014).

  161. 161.

    Zhang, Y. et al. Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs. Nat. Cell Biol. 20, 535–540 (2018). This study describes the key role of the tRNA methyltransferase DNMT2 in the transmission of metabolic phenotypes in mice.

  162. 162.

    Houwing, S. et al. A role for Piwi and piRNAs in germ cell maintenance and transposon silencing in zebrafish. Cell 129, 69–82 (2007).

  163. 163.

    Tang, F. et al. Maternal microRNAs are essential for mouse zygotic development. Genes Dev. 21, 644–648 (2007).

  164. 164.

    Jonkhout, N. et al. The RNA modification landscape in human disease. RNA 23, 1754–1769 (2017).

  165. 165.

    Erhardt, S. et al. Consequences of the depletion of zygotic and embryonic enhancer of zeste 2 during preimplantation mouse development. Development 130, 4235–4248 (2003).

  166. 166.

    Posfai, E. et al. Polycomb function during oogenesis is required for mouse embryonic development. Genes Dev. 26, 920–932 (2012).

  167. 167.

    Andreu-Vieyra, C. V. et al. MLL2 is required in oocytes for bulk histone 3 lysine 4 trimethylation and transcriptional silencing. PLOS Biol. 8, e1000453 (2010).

  168. 168.

    Liu, X. et al. Distinct features of H3K4me3 and H3K27me3 chromatin domains in pre-implantation embryos. Nature 537, 558–562 (2016).

  169. 169.

    Yuan, S. et al. Sperm-borne mi-RNAs and endo-siRNAs are important for fertilization and preimplantation embryonic development. Development 143, 635–647 (2016).

  170. 170.

    Giraldez, A. J. et al. MicroRNAs regulate brain morphogenesis in zebrafish. Science 308, 833–838 (2005).

  171. 171.

    Conine, C. C., Sun, F., Song, L., Rivera-Perez, J. A. & Rando, O. J. Small RNAs gained during epididymal transit of sperm are essential for embryonic development in mice. Dev. Cell 46, 470–480 (2018).

  172. 172.

    Sharma, U. et al. Small RNAs are trafficked from the epididymis to developing mammalian sperm. Dev. Cell 46, 481–494 (2018).

  173. 173.

    Ost, A. et al. Paternal diet defines offspring chromatin state and intergenerational obesity. Cell 159, 1352–1364 (2014).

  174. 174.

    Filion, G. J. et al. Systematic protein location mapping reveals five principal chromatin types in Drosophila cells. Cell 143, 212–224 (2010).

  175. 175.

    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).

  176. 176.

    Martinez, D. et al. In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving altered Lxra DNA methylation. Cell Metab. 19, 941–951 (2014).

  177. 177.

    Cubas, P., Vincent, C. & Coen, E. An epigenetic mutation responsible for natural variation in floral symmetry. Nature 401, 157–161 (1999).

  178. 178.

    Shea, J. M. et al. Genetic and epigenetic variation, but not diet, shape the sperm methylome. Dev. Cell 35, 750–758 (2015).

  179. 179.

    Liu, X. S. et al. Editing DNA methylation in the mammalian genome. Cell 167, 233–247 (2016).

  180. 180.

    Vojta, A. et al. Repurposing the CRISPR-Cas9 system for targeted DNA methylation. Nucleic Acids Res. 44, 5615–5628 (2016).

  181. 181.

    Pflueger, C. et al. A modular dCas9-SunTag DNMT3A epigenome editing system overcomes pervasive off-target activity of direct fusion dCas9-DNMT3A constructs. Genome Res. 28, 1193–1206 (2018).

  182. 182.

    Kwon, D. Y., Zhao, Y. T., Lamonica, J. M. & Zhou, Z. Locus-specific histone deacetylation using a synthetic CRISPR-Cas9-based HDAC. Nat. Commun. 8, 15315 (2017).

  183. 183.

    Ragunathan, K., Jih, G. & Moazed, D. Epigenetics. Epigenetic inheritance uncoupled from sequence-specific recruitment. Science 348, 1258699 (2015).

  184. 184.

    Bannister, A. J. & Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res. 21, 381–395 (2011).

  185. 185.

    Meaney, M. J. Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu. Rev. Neurosci. 24, 1161–1192 (2001).

  186. 186.

    Goll, M. G. & Bestor, T. H. Eukaryotic cytosine methyltransferases. Annu. Rev. Biochem. 74, 481–514 (2005).

  187. 187.

    Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).

  188. 188.

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

  189. 189.

    Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).

  190. 190.

    Schultz, D. C., Ayyanathan, K., Negorev, D., Maul, G. G. & Rauscher, F. J. 3rd. SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev. 16, 919–932 (2002).

  191. 191.

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

  192. 192.

    Lachner, M., O’Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).

  193. 193.

    Bernstein, E. et al. Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin. Mol. Cell. Biol. 26, 2560–2569 (2006).

  194. 194.

    Czermin, B. et al. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 111, 185–196 (2002).

  195. 195.

    Kuzmichev, A., Nishioka, K., Erdjument-Bromage, H., Tempst, P. & Reinberg, D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 16, 2893–2905 (2002).

  196. 196.

    Birve, A. et al. Su(z)12, a novel Drosophila Polycomb group gene that is conserved in vertebrates and plants. Development 128, 3371–3379 (2001).

  197. 197.

    Pasini, D., Bracken, A. P., Jensen, M. R., Lazzerini Denchi, E. & Helin, K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 23, 4061–4071 (2004).

  198. 198.

    Margueron, R. et al. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461, 762–767 (2009).

  199. 199.

    Simon, J., Chiang, A., Bender, W., Shimell, M. J. & O’Connor, M. Elements of the Drosophila bithorax complex that mediate repression by Polycomb group products. Dev. Biol. 158, 131–144 (1993).

  200. 200.

    Chan, C. S., Rastelli, L. & Pirrotta, V. A. Polycomb response element in the Ubx gene that determines an epigenetically inherited state of repression. EMBO J. 13, 2553–2564 (1994).

  201. 201.

    Perino, M. et al. MTF2 recruits Polycomb Repressive Complex 2 by helical-shape-selective DNA binding. Nat. Genet. 50, 1002–1010 (2018).

  202. 202.

    Santos-Rosa, H. et al. Active genes are tri-methylated at K4 of histone H3. Nature 419, 407–411 (2002).

  203. 203.

    Bernstein, B. E. et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120, 169–181 (2005).

  204. 204.

    Koch, C. M. et al. The landscape of histone modifications across 1% of the human genome in five human cell lines. Genome Res. 17, 691–707 (2007).

  205. 205.

    Shilatifard, A. The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu. Rev. Biochem. 81, 65–95 (2012).

  206. 206.

    Kim, V. N., Han, J. & Siomi, M. C. Biogenesis of small RNAs in animals. Nat. Rev. Mol. Cell Biol. 10, 126–139 (2009).

  207. 207.

    Goll, M. G. et al. Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 311, 395–398 (2006).

  208. 208.

    Hock, J. & Meister, G. The Argonaute protein family. Genome Biol. 9, 210 (2008).

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The authors thank J. Cropley, F. Zenk, A. Ashe and R. Lister for comments on the manuscript. The authors apologize to colleagues whose work could not be cited owing to space limitations.

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Nature Reviews Molecular Cell Biology thanks O. Rechavi and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    • Ksenia Skvortsova
    •  & Ozren Bogdanović
  2. Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany

    • Nicola Iovino
  3. St Vincent’s Clinical School, University of New South Wales–Sydney, Sydney, New South Wales, Australia

    • Ozren Bogdanović


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All authors contributed to researching data for the article, discussion of content and the writing and editing of the manuscript.

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The authors declare no competing interests.

Corresponding authors

Correspondence to Nicola Iovino or Ozren Bogdanović.

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Spanning more than two generations, from F0 to F2 and beyond.

Intergenerational epigenetic inheritance

Inheritance of an epigenetic trait across two generations, from F0 to F1.

Facultative heterochromatin

Condensed, transcriptionally silent chromatin that retains the ability to decondense and license transcription within temporal and spatial contexts.

PIWI-interacting RNAs

(piRNAs). A class of endogenous small non-coding RNAs that interact with Piwi-domain-containing proteins and have a role in retrotransposon silencing in the germ line.

Primordial germ cells

(PGCs). Primary germ cells that give rise to gametes.

Imprinting control regions

cis-regulatory regions for which the allele-specific epigenetic state mediates differential expression of the parental alleles.

Prader–Willi syndrome

A complex disorder characterized by developmental and neural phenotypes that can be caused by a paternal imprinting defect.

Angelman syndrome

A neurological disorder characterized by intellectual disability that can be caused by a maternal imprinting defect.

Bisulfite sequencing

Treatment of DNA with sodium bisulfite followed by sequencing; determines cytosine methylation status, as unmethylated cytosine is converted into uracil upon this treatment.


Genetically identical alleles displaying distinct epigenetic modifications.


Heritable changes in gene expression that are caused by changes in the epigenetic state.

Microsatellite instability

Genetic instability in short tandem repeats due to impaired DNA mismatch repair.

Differentially methylated region

(DMR). A genomic region displaying statistically significant change in DNA methylation between at least two samples.

Ten-eleven translocation (TET) enzymes

Enzymes required for active DNA demethylation, which catalyse a series of iterative oxidations of 5-methylcytosine to 5-hydroxymethylcytosine and further to 5-formylcytosine and 5-carboxylcytosine.

CpG islands

Genomic regions of high GC content and high frequency of CpG sites relative to the genome average; often associated with gene promoters and maintained in an unmethylated state.

Zygotic genome activation

(ZGA). Activation of zygotic genome transcription for the first time after fertilization.

Constitutive heterochromatin

Highly condensed, permanently transcriptionally silent late-replicating chromatin.


Heritable change in gene expression of a (paramutable) allele, which is mediated by trans-interaction with the homologous (paramutagenic) allele.

Homeotic transformation

The formation of a body structure or an organ in place of another in an abnormal location.

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