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.

Molecular mechanisms of transgenerational epigenetic inheritance

Abstract

Increasing evidence indicates that non-DNA sequence-based epigenetic information can be inherited across several generations in organisms ranging from yeast to plants to humans. This raises the possibility of heritable ‘epimutations’ contributing to heritable phenotypic variation and thus to evolution. Recent work has shed light on both the signals that underpin these epimutations, including DNA methylation, histone modifications and non-coding RNAs, and the mechanisms by which they are transmitted across generations at the molecular level. These mechanisms can vary greatly among species and have a more limited effect in mammals than in plants and other animal species. Nevertheless, common principles are emerging, with transmission occurring either via direct replicative mechanisms or indirect reconstruction of the signal in subsequent generations. As these processes become clearer we continue to improve our understanding of the distinctive features and relative contribution of DNA sequence and epigenetic variation to heritable differences in phenotype.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Intergenerational and transgenerational epigenetic inheritance.
Fig. 2: Replicative and reconstructive inheritance.
Fig. 3: Paramutation: horizontal transfer of epigenetic information.

References

  1. Cavalli, G. & Heard, E. Advances in epigenetics link genetics to the environment and disease. Nature 571, 489–499 (2019).

    Article  CAS  PubMed  Google Scholar 

  2. Grewal, S. I. S. & Klar, A. J. S. Chromosomal inheritance of epigenetic states in fission yeast during mitosis and meiosis. Cell 86, 95–101 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Ekwall, K., Olsson, T., Turner, B. M., Cranston, G. & Allshire, R. C. Transient inhibition of histone deacetylation alters the structural and functional imprint at fission yeast centromeres. Cell 91, 1021–1032 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Heard, E. & Martienssen, R. A. Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157, 95–109 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Skvortsova, K., Iovino, N. & Bogdanović, O. Functions and mechanisms of epigenetic inheritance in animals. Nat. Rev. Mol. Cell Biol. 19, 774–790 (2018).

    Article  CAS  PubMed  Google Scholar 

  8. Perez, M. F. & Lehner, B. Intergenerational and transgenerational epigenetic inheritance in animals. Nat. Cell Biol. 21, 143–151 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Birney, E., Smith, G. D. & Greally, J. M. Epigenome-wide association studies and the interpretation of disease -omics. PLoS Genet. 12, 1–9 (2016).

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. da Cruz, R. S., Chen, E., Smith, M., Bates, J. & de Assis, S. Diet and transgenerational epigenetic inheritance of breast cancer: the role of the paternal germline. Front. Nutr. 7, 93 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. King, S. E. & Skinner, M. K. Epigenetic transgenerational inheritance of obesity susceptibility. Trends Endocrinol. Metab. 31, 478–494 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sarkies, P. Molecular mechanisms of epigenetic inheritance: possible evolutionary implications. Semin. Cell Dev. Biol. 97, 106–115 (2020). A good overview of the potential role of TEI in evolution and adaptation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bošković, A. & Rando, O. J. Transgenerational epigenetic inheritance. Annu. Rev. Genet. 52, 21–41 (2018).

    Article  PubMed  CAS  Google Scholar 

  15. Leroux, S. et al. Embryonic environment and transgenerational effects in quail. Genet. Sel. Evol. 49, 14 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Pierron, F. et al. Transgenerational epigenetic sex determination: environment experienced by female fish affects offspring sex ratio. Environ. Pollut. 277, 116864 (2021).

    Article  CAS  PubMed  Google Scholar 

  17. Beck, D., Ben Maamar, M. & Skinner, M. K. Integration of sperm ncRNA-directed DNA methylation and DNA methylation-directed histone retention in epigenetic transgenerational inheritance. Epigenetics Chromatin 14, 6 (2021). A follow-up to Skinner et al. (2018), which implicates ncRNA, DNA methylation and sperm histone retention at the same loci but in different generations in TEI, suggesting a layered response to environmental insults.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bertozzi, T. M. & Ferguson-Smith, A. C. Metastable epialleles and their contribution to epigenetic inheritance in mammals. Semin. Cell Dev. Biol. 97, 93–105 (2020).

    Article  CAS  PubMed  Google Scholar 

  19. Kazachenka, A. et al. Identification, characterization, and heritability of murine metastable epialleles: implications for non-genetic inheritance. Cell 175, 1259–1271.e13 (2018). A screen for murine metastable epialleles identifying 87 candidates, although experimental validation shows that not all are involved in TEI.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bertozzi, T. M., Elmer, J. L., Macfarlan, T. S. & Ferguson-Smith, A. C. KRAB zinc finger protein diversification drives mammalian interindividual methylation variability. Proc. Natl Acad. Sci. USA 117, 31290–31300 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schmitz, R. J. et al. Patterns of population epigenomic diversity. Nature 495, 193–198 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kawakatsu, T. et al. Epigenomic diversity in a global collection of Arabidopsis thaliana accessions. Cell 166, 492–505 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Johannes, F. et al. Assessing the impact of transgenerational epigenetic variation on complex traits. PLoS Genet. 5, e1000530 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Cubas, P. et al. An epigenetic mutation responsible for natural variation in floral symmetry. Nature 401, 157–161 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Manning, K. et al. A naturally occurring epigenetic mutation in a gene encoding an SBP-box transcription factor inhibits tomato fruit ripening. Nat. Genet. 38, 948–952 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Fujimoto, R. et al. Evolution and control of imprinted FWA genes in the genus Arabidopsis. PLoS Genet. 4, e1000048 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Roux, F. et al. Genome-wide epigenetic perturbation jump-starts patterns of heritable variation found in nature. Genetics 188, 1015–1017 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Furci, L. et al. Identification and characterisation of hypomethylated DNA loci controlling quantitative resistance in Arabidopsis. eLife 8, e40655 (2019). Roux et al. (2011) and Furci et al. (2019) illustrate the probably widespread role of heritable DNA methylation in plant quantitative trait variation.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Fanti, L., Piacentini, L., Cappucci, U., Casale, A. M. & Pimpinelli, S. Canalization by selection of de novo induced mutations. Genetics 206, 1995–2006 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Audergon, P. N. C. B. et al. Restricted epigenetic inheritance of H3K9 methylation. Science 348, 132–135 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ciabrelli, F. et al. Stable Polycomb-dependent transgenerational inheritance of chromatin states in Drosophila. Nat. Genet. 49, 876–886 (2017). An intriguing example of a very stable epiallele in D. melanogaster that can be selected for both up- and down-regulation of a transgene, and which implicates H3K27me3 and 3D chromatin contacts.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rose, N. R. & Klose, R. J. Understanding the relationship between DNA methylation and histone lysine methylation. Biochim. Biophys. Acta 1839, 1362–1372 (2014).

    Article  CAS  PubMed  Google Scholar 

  34. Daxinger, L. et al. Hypomethylation of ERVs in the sperm of mice haploinsufficient for the histone methyltransferase Setdb1 correlates with a paternal effect on phenotype. Sci. Rep. 6, 1–10 (2016).

    Article  CAS  Google Scholar 

  35. Torres-Garcia, S. et al. Epigenetic gene silencing by heterochromatin primes fungal resistance. Nature 585, 453–458 (2020). This study tracks the establishment of a heterochromatin-based epimutation in response to an environmental insult in fission yeast, providing evidence of TEI as an adaptation to a changing environment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yu, R., Wang, X. & Moazed, D. Epigenetic inheritance mediated by coupling of RNAi and histone H3K9 methylation. Nature 558, 615–619 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. Klosin, A., Casas, E., Hidalgo-Carcedo, C., Vavouri, T. & Lehner, B. Transgenerational transmission of environmental information in C. elegans. Science 356, 320–323 (2017).

    Article  CAS  PubMed  Google Scholar 

  39. Greer, E. L. et al. Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466, 383–387 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Siklenka, K. et al. Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science 350, aab2006 (2015).

    Article  PubMed  CAS  Google Scholar 

  41. Lismer, A., Siklenka, K., Lafleur, C., Dumeaux, V. & Kimmins, S. Sperm histone H3 lysine 4 trimethylation is altered in a genetic mouse model of transgenerational epigenetic inheritance. Nucleic Acids Res. 48, 11380–11393 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Duempelmann, L., Skribbe, M. & Bühler, M. Small RNAs in the transgenerational inheritance of epigenetic information. Trends Genet. 36, 203–214 (2020).

    Article  CAS  PubMed  Google Scholar 

  43. Czech, B. et al. piRNA-guided genome defense: from biogenesis to silencing. Annu. Rev. Genet. 52, 131–157 (2018).

    Article  CAS  PubMed  Google Scholar 

  44. Luteijn, M. J. & Ketting, R. F. PIWI-interacting RNAs: from generation to transgenerational epigenetics. Nat. Rev. Genet. 14, 523–534 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. O’Brien, J., Hayder, H., Zayed, Y. & Peng, C. Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol. 9, 402 (2018).

    Article  Google Scholar 

  46. Calo, S. et al. Antifungal drug resistance evoked via RNAi-dependent epimutations. Nature 513, 555–558 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Calo, S. et al. A non-canonical RNA degradation pathway suppresses RNAi-dependent epimutations in the human fungal pathogen Mucor circinelloides. PLoS Genet. 13, 1–26 (2017).

    Article  CAS  Google Scholar 

  48. Gehring, M. Epigenetic dynamics during flowering plant reproduction: evidence for reprogramming? N. Phytol. 224, 91–96 (2019).

    Article  Google Scholar 

  49. Calarco, J. P. et al. Reprogramming of DNA methylation in pollen guides epigenetic inheritance via small RNA. Cell 151, 194–205 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Long, J. et al. Nurse cell-derived small RNAs define paternal epigenetic inheritance in Arabidopsis. Science 373, eabh0556 (2021).

    Article  CAS  PubMed  Google Scholar 

  51. Cox, D. N. et al. A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal. Genes Dev. 12, 3715–3727 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Aravin, A. A., Hannon, G. J. & Brennecke, J. The Piwi-piRNA pathway provides an adaptive defense in the transposon arms race. Science 318, 761–764 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Le Thomas, A. et al. Piwi induces piRNA-guided transcriptional silencing and establishment of a repressive chromatin state. Genes Dev. 27, 390–399 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Yu, Y. et al. Panoramix enforces piRNA-dependent cotranscriptional silencing. Science 350, 339–342 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mugat, B. et al. The Mi-2 nucleosome remodeler and the Rpd3 histone deacetylase are involved in piRNA-guided heterochromatin formation. Nat. Commun. 11, 2818 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Klattenhoff, C. et al. The Drosophila HP1 homolog rhino is required for transposon silencing and piRNA production by dual-strand clusters. Cell 138, 1137–1149 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Andersen, P. R., Tirian, L., Vunjak, M. & Brennecke, J. A heterochromatin-dependent transcription machinery drives piRNA expression. Nature 549, 54–59 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rozhkov, N. V. et al. Small RNA-based silencing strategies for transposons in the process of invading Drosophila species. RNA 16, 1634–1645 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Le Thomas, A., Marinov, G. K. & Aravin, A. A. A transgenerational process defines piRNA biogenesis in Drosophila virilis. Cell Rep. 8, 1617–1623 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Grentzinger, T. et al. PiRNA-mediated transgenerational inheritance of an acquired trait. Genome Res. 22, 1877–1888 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mao, H. et al. The Nrde pathway mediates small-RNA-directed histone H3 lysine 27 trimethylation in Caenorhabditis elegans. Curr. Biol. 25, 2398–2403 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Schwartz-Orbach, L. et al. Caenorhabditis elegans nuclear RNAi factor SET-32 deposits the transgenerational histone modification, H3K23me3. eLife 9, e54309 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  64. Vastenhouw, N. L. et al. Long-term gene silencing by RNAi. Nature 442, 882–882 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Buckley, B. A. et al. A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality. Nature 489, 447–451 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Shirayama, M. et al. PiRNAs initiate an epigenetic memory of nonself RNA in the C. elegans germline. Cell 150, 65–77 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Schott, D., Yanai, I. & Hunter, C. P. Natural RNA interference directs a heritable response to the environment. Sci. Rep. 4, 7387 (2015).

    Article  CAS  Google Scholar 

  71. Kaletsky, R. et al. C. elegans interprets bacterial non-coding RNAs to learn pathogenic avoidance. Nature 586, 445–451 (2020). An intriguing case of an exogenous source of small RNAs triggering siRNA silencing of an endogenous neuronal gene over several generations in C. elegans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Posner, R. et al. Neuronal small RNAs control behavior transgenerationally. Cell 177, 1814–1826 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Almeida, M. V., Andrade-Navarro, M. A. & Ketting, R. F. Function and evolution of nematode RNAi pathways. Non Coding RNA 5, 8 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  74. Barucci, G. et al. Small-RNA-mediated transgenerational silencing of histone genes impairs fertility in piRNA mutants. Nat. Cell Biol. 22, 235–245 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Quarato, P. et al. Germline inherited small RNAs facilitate the clearance of untranslated maternal mRNAs in C. elegans embryos. Nat. Commun. 12, 1441 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chen, Q., Yan, W. & Duan, E. Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications. Nat. Rev. Genet. 17, 733–743 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Paris, L. et al. Transgenerational inheritance of enhanced susceptibility to radiation-induced medulloblastoma in newborn Ptch1+/− mice after paternal irradiation. Oncotarget 6, 36098–36112 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Rodgers, A. B., Morgan, C. P., Bronson, S. L., Revello, S. & Bale, T. L. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J. Neurosci. 33, 9003–9012 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Fullston, T. et al. Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB J. 27, 4226–4243 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. 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). One of the first studies to show that injection of sperm ncRNAs can recapitulate behavioural phenotypes in another individual.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gapp, K. et al. Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma. Mol. Psychiat. 25, 2162–2174 (2020).

    Article  CAS  Google Scholar 

  82. Grandjean, V. et al. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci. Rep. 5, 18193 (2016).

    Article  CAS  Google Scholar 

  83. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Miska, E. A. & Ferguson-smith, A. C. Transgenerational inheritance: models and mechanisms of non-DNA sequence-based inheritance. Science 354, 778–782 (2016).

    Article  CAS  Google Scholar 

  85. Day, J. J. & Sweatt, J. D. DNA methylation and memory formation. Nat. Neurosci. 13, 1319–1323 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Petryk, N. et al. MCM2 promotes symmetric inheritance of modified histones during DNA replication. Science 361, 1389–1392 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Reverón-Gómez, N. et al. Accurate recycling of parental histones reproduces the histone modification landscape during DNA replication. Mol. Cell 72, 239–249 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Escobar, T. M. et al. Active and repressed chromatin domains exhibit distinct nucleosome segregation during DNA replication. Cell 179, 953–963 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Alabert, C. et al. Domain model explains propagation dynamics and stability of histone H3K27 and H3K36 methylation landscapes. Cell Rep. 30, 1223–1234 (2020).

    Article  CAS  PubMed  Google Scholar 

  90. O’Kane, C. J. & Hyland, E. M. Yeast epigenetics: the inheritance of histone modification states. Biosci. Rep. 39, 1–13 (2019).

    Article  Google Scholar 

  91. Morgan, H. D., Santos, F., Green, K., Dean, W. & Reik, W. Epigenetic reprogramming in mammals. Hum. Mol. Genet. 14, 47–58 (2005).

    Article  CAS  Google Scholar 

  92. Nakamura, T. et al. PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos. Nature 486, 415–419 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Li, X. et al. A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. Dev. Cell 15, 547–557 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Messerschmidt, D. M. et al. Trim28 is required for epigenetic stability during mouse oocyte to embryo transition. Science 335, 1499–1502 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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, 399–405 (2006).

    Article  CAS  Google Scholar 

  98. Fernandez-Gonzalez, R., Ramirez, M. A., Pericuesta, E., Calle, A. & Gutierrez-Adan, A. Histone modifications at the blastocyst Axin1Fu locus mark the heritability of in vitro culture-induced epigenetic alterations in mice. Biol. Reprod. 83, 720–727 (2010).

    Article  CAS  PubMed  Google Scholar 

  99. Gu, L., Wang, Q. & Sun, Q. Y. Histone modifications during mammalian oocyte maturation: dynamics, regulation and functions. Cell Cycle 9, 1942–1950 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Hanna, C. W. et al. MLL2 conveys transcription-independent H3K4 trimethylation in oocytes. Nat. Struct. Mol. Biol. 25, 73–82 (2018).

    Article  CAS  PubMed  Google Scholar 

  101. Fraser, R. & Lin, C.-J. Epigenetic reprogramming of the zygote in mice and men: on your marks, get set, go! Reproduction 152, R211–R222 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Wu, J. et al. Chromatin analysis in human early development reveals epigenetic transition during ZGA. Nature 557, 256–260 (2018).

    Article  CAS  PubMed  Google Scholar 

  103. Liu, B. et al. The landscape of RNA Pol II binding reveals a stepwise transition during ZGA. Nature 587, 139–144 (2020).

    Article  CAS  PubMed  Google Scholar 

  104. Gold, H. B., Jung, Y. H. & Corces, V. G. Not just heads and tails: the complexity of the sperm epigenome. J. Biol. Chem. 293, 13815–13820 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 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).

    Article  CAS  PubMed  Google Scholar 

  107. Jung, Y. H. et al. Chromatin states in mouse sperm correlate with embryonic and adult regulatory landscapes. Cell Rep. 18, 1366–1382 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kremsky, I. & Corces, V. G. Protection from DNA re-methylation by transcription factors in primordial germ cells and pre-implantation embryos can explain trans-generational epigenetic inheritance. Genome Biol. 21, 118 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Roovers, E. F. et al. Piwi proteins and piRNAs in mammalian oocytes and early embryos. Cell Rep. 10, 2069–2082 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Conine, C. C., Sun, F., Song, L., Rivera-Pérez, 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sharma, U. et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351, 391–396 (2016).

    Article  CAS  PubMed  Google Scholar 

  117. Zhang, X. et al. Systematic identification and characterization of long non-coding RNAs in mouse mature sperm. PLoS ONE 12, e0173402 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Lev, I. & Rechavi, O. Germ granules allow transmission of small RNA-based parental responses in the “germ plasm”. iScience 23, 101831 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Dodson, A. E. & Kennedy, S. K. Germ granules coordinate RNA-based epigenetic inheritance pathways. Dev. Cell 50, 704–715 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Lev, I. et al. Germ granules govern small RNA inheritance. Curr. Biol. 29, 2880–2891 (2019). Dodson et al. (2019) and Lev et al. (2019) show the involvement of germ granules in small RNA inheritance and TEI in C. elegans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Voronina, E., Seydoux, G., Sassone-Corsi, P. & Nagamori, I. RNA granules in germ cells. Cold Spring Harb. Perspect. Biol. 3, a002774–a002774 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Banani, S. F., Lee, H. O., Hyman, A. A. & Rosen, M. K. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18, 285–298 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Dodson, A. E. & Kennedy, S. Phase separation in germ cells and development. Dev. Cell 55, 4–17 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bonev, B. & Cavalli, G. Organization and function of the 3D genome. Nat. Rev. Genet. 17, 661–678 (2016).

    Article  CAS  PubMed  Google Scholar 

  125. van Steensel, B. & Belmont, A. S. Lamina-associated domains: links with chromosome architecture, heterochromatin, and gene repression. Cell 169, 780–791 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Robson, M. I. et al. Tissue-specific gene repositioning by muscle nuclear membrane proteins enhances repression of critical developmental genes during myogenesis. Mol. Cell 62, 834–847 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Holla, S. et al. Positioning heterochromatin at the nuclear periphery suppresses histone turnover to promote epigenetic inheritance. Cell 180, 150–164 (2020).

    Article  CAS  PubMed  Google Scholar 

  128. Sun, J., Shi, Y. & Yildirim, E. The nuclear pore complex in cell type-specific chromatin structure and gene regulation. Trends Genet. 35, 579–588 (2019).

    Article  CAS  PubMed  Google Scholar 

  129. Schuettengruber, B., Bourbon, H. M., Di Croce, L. & Cavalli, G. Genome regulation by Polycomb and Trithorax: 70 years and counting. Cell 171, 34–57 (2017).

    Article  CAS  PubMed  Google Scholar 

  130. Yin, Y. et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science 356, eaaj2239 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Wolstenholme, J. T. et al. Gestational exposure to bisphenol a produces transgenerational changes in behaviors and gene expression. Endocrinology 153, 3828–3838 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Jung, Y. H. et al. Recruitment of CTCF to an Fto enhancer is responsible for transgenerational inheritance of obesity. Preprint at bioRxiv https://doi.org/10.1101/2020.11.20.391672 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Loos, R. J. F. & Yeo, G. S. H. The bigger picture of FTO — The first GWAS-identified obesity gene. Nat. Rev. Endocrinol. 10, 51–61 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Hollick, J. B. Paramutation and related phenomena in diverse species. Nat. Rev. Genet. 18, 5–23 (2016). A good review on paramutation with a focus on plants, but touching on other organisms as well.

    Article  PubMed  CAS  Google Scholar 

  135. Pilu, R. Paramutation phenomena in plants. Semin. Cell Dev. Biol. 44, 2–10 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  138. Hermant, C. et al. Paramutation in Drosophila requires both nuclear and cytoplasmic actors of the piRNA pathway and induces cis-spreading of piRNA production. Genetics 201, 1381–1396 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  141. Yuan, S., Oliver, D., Schuster, A., Zheng, H. & Yan, W. Breeding scheme and maternal small RNAs affect the efficiency of transgenerational inheritance of a paramutation in mice. Sci. Rep. 5, 9266 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ronsseray, S. Paramutation phenomena in non-vertebrate animals. Semin. Cell Dev. Biol. 44, 39–46 (2015).

    Article  PubMed  Google Scholar 

  143. Apte, M. S. & Meller, V. H. Homologue pairing in flies and mammals: gene regulation when two are involved. Genet. Res. Int. 2012, 430587 (2012).

    PubMed  Google Scholar 

  144. Fukaya, T. & Levine, M. Transvection. Curr. Biol. 27, R1047–R1049 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Hoencamp, C. et al. 3D genomics across the tree of life reveals condensin II as a determinant of architecture type. Science 372, 984–989 (2021).

    Article  CAS  PubMed  Google Scholar 

  146. Bente, H., Foerster, A. M., Lettner, N. & Mittelsten Scheid, O. Polyploidy-associated paramutation in Arabidopsis is determined by small RNAs, temperature, and allele structure. PLoS Genet. 17, e1009444 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Thorson, J. L. M., Beck, D., Ben Maamar, M., Nilsson, E. E. & Skinner, M. K. Ancestral plastics exposure induces transgenerational disease-specific sperm epigenome-wide association biomarkers. Environ. Epigenetics 7, dvaa023 (2021).

    Article  CAS  Google Scholar 

  148. Silveira, A. B. et al. Extensive natural epigenetic variation at a de novo originated gene. PLoS Genet. 9, e1003437 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Alonso, C., Pérez, R., Bazaga, P., Medrano, M. & Herrera, C. M. Individual variation in size and fecundity is correlated with differences in global DNA cytosine methylation in the perennial herb Helleborus foetidus (Ranunculaceae). Am. J. Bot. 101, 1309–1313 (2014).

    Article  PubMed  Google Scholar 

  150. Skinner, M. K. et al. Alterations in sperm DNA methylation, non-coding RNA and histone retention associate with DDT-induced epigenetic transgenerational inheritance of disease. Epigenetics Chromatin 11, 8 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Bogdanović, O. & Veenstra, G. J. C. DNA methylation and methyl-CpG binding proteins: developmental requirements and function. Chromosoma 118, 549–565 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Zhang, H., Lang, Z. & Zhu, J. K. Dynamics and function of DNA methylation in plants. Nat. Rev. Mol. Cell Biol. 19, 489–506 (2018).

    Article  CAS  PubMed  Google Scholar 

  154. Du, Q., Luu, P. L., Stirzaker, C. & Clark, S. J. Methyl-CpG-binding domain proteins: readers of the epigenome. Epigenomics 7, 1051–1073 (2015).

    Article  CAS  PubMed  Google Scholar 

  155. 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).

    Article  CAS  PubMed  Google Scholar 

  156. Martire, S. & Banaszynski, L. A. The roles of histone variants in fine-tuning chromatin organization and function. Nat. Rev. Mol. Cell Biol. 21, 522–541 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Allis, C. D. & Jenuwein, T. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 17, 487–500 (2016).

    Article  CAS  PubMed  Google Scholar 

  158. Allshire, R. C. & Madhani, H. D. Ten principles of heterochromatin formation and function. Nat. Rev. Mol. Cell Biol. 19, 229–244 (2018).

    Article  CAS  PubMed  Google Scholar 

  159. Kim, J. & Kim, H. Recruitment and biological consequences of histone modification of H3K27me3 and H3K9me3. ILAR J. 53, 232–239 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Blackledge, N. P., Rose, N. R. & Klose, R. J. Targeting Polycomb systems to regulate gene expression: modifications to a complex story. Nat. Rev. Mol. Cell Biol. 16, 643–649 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Jonas, S. & Izaurralde, E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat. Rev. Genet. 16, 421–433 (2015).

    Article  CAS  PubMed  Google Scholar 

  162. Xiao, M. et al. MicroRNAs activate gene transcription epigenetically as an enhancer trigger. RNA Biol. 14, 1326–1334 (2017).

    Article  PubMed  Google Scholar 

  163. Miao, L. et al. A dual inhibition: microRNA-552 suppresses both transcription and translation of cytochrome P450 2E1. Biochim. Biophys. Acta 1859, 650–662 (2016).

    Article  CAS  PubMed  Google Scholar 

  164. Nishi, K., Nishi, A., Nagasawa, T. & Ui-Tei, K. Human TNRC6A is an Argonaute-navigator protein for microRNA-mediated gene silencing in the nucleus. RNA 19, 17–35 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Benhamed, M., Herbig, U., Ye, T., Dejean, A. & Bischof, O. Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells. Nat. Cell Biol. 14, 266–275 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Schmitz, S. U., Grote, P. & Herrmann, B. G. Mechanisms of long noncoding RNA function in development and disease. Cell. Mol. Life Sci. 73, 2491–2509 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Peng, H. et al. A novel class of tRNA-derived small RNAs extremely enriched in mature mouse sperm. Cell Res. 22, 1609–1612 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

M.H.F.-J. was supported by the MSDAVENIR foundation (project GENE-IGH) and by a grant from the European Research Council (Advanced Grant 3DEpi, under grant agreement number 788972). The laboratory of G.C. was supported by grants from the European Research Council (Advanced Grant 3DEpi, under grant agreement number 788972), the European Union (CHROMDESIGN Project, under the Marie Skłodowska-Curie grant agreement number 813327), the Fondation pour la Recherche Médicale (DEI20151234396), the MSDAVENIR foundation (project GENE-IGH), the INSERM, the Centre National pour la Recherche Scientifique, the Agence Nationale de la Recherche (E-RARE project ‘IMPACT’) and the French National Cancer Institute (INCa PLBIO18-362).

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Giacomo Cavalli.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Genetics thanks V. Colot and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Epigenetic

Mitotically or meiotically heritable gene regulatory information that is independent of changes in DNA sequence.

Intergenerational epigenetic inheritance

Transmission of epigenetic information from parent to offspring to the F1 or F2 generations when the signal originated in males or females, respectively.

Transgenerational epigenetic inheritance

(TEI). Transmission of epigenetic information across generations beyond the limit of intergenerational epigenetic inheritance.

Epimutations

Heritable epigenetic changes, usually causing an observable phenotype.

Metastable epialleles

Genetically identical alleles that are variably expressed owing to epigenetic factors in genetically identical individuals.

Epigenetic recombinant inbred lines

(epiRILs). Inbred plant strains with different DNA methylation profiles obtained from a cross between two parents from the same genetic background of whom one bears a mutation in a DNA methylation gene.

Quantitative trait loci

(QTLs). Loci where genetic variation correlates with variation in a quantitative, non-discrete phenotype.

Small RNA

Technically refers to RNA molecules under 200 nucleotides in length. More commonly refers to a diverse set of 19–36-nucleotide RNAs implicated in gene regulation, including small interfering RNAs (siRNAs), PIWI-interacting RNAs (piRNAs) and microRNAs (miRNAs).

Long non-coding RNAs

(lncRNAs). RNA molecules longer than 200 nucleotides that are not translated into proteins.

Paramutation

Horizontal transmission of a heritable epigenetic state from one allele of a locus to the other.

Germ granules

Membraneless cytoplasmic organelles found in metazoan germ cells.

Transvection

A process that is common in Drosophila species by which one allele of a gene or its regulatory sequence on one chromosome can regulate the transcription of its homologue on the other chromosome in trans, mediated by pairing of the two loci.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fitz-James, M.H., Cavalli, G. Molecular mechanisms of transgenerational epigenetic inheritance. Nat Rev Genet 23, 325–341 (2022). https://doi.org/10.1038/s41576-021-00438-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41576-021-00438-5

This article is cited by

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