Abstract
Epigenetic modifications direct the way DNA is packaged into the nucleus, making genes more or less accessible to transcriptional machinery and influencing genomic stability. Environmental factors have the potential to alter the epigenome, allowing genes that are silenced to be activated and vice versa. This ultimately influences disease susceptibility and health in an individual. Furthermore, altered chromatin states can be transmitted to subsequent generations, thus epigenetic modifications may provide evolutionary mechanisms that impact on adaptation to changed environments. However, the mechanisms involved in establishing and maintaining these epigenetic modifications during development remain unclear. This review discusses current evidence for transgenerational epigenetic inheritance, confounding issues associated with its study, and the biological relevance of altered epigenetic states for subsequent generations.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 Epigenetic reprogramming in mouse primordial germ cells. Mech. Dev. 117(1–2), 15–23 (2002).• Demonstrates epigenetic reprogramming in primordial germ cells (PGCs).
- 2 . Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells. Development 139(1), 15–31 (2012).
- 3 . Epigenetic reprogramming in mammals. Hum. Mol. Genet. 14(Suppl. 1), R47–R58 (2005).
- 4 . Epigenetic reprogramming in plant and animal development. Science 330(6004), 622–627 (2010).
- 5 . Transgenerational epigenetics in the germline cycle of Caenorhabditis elegans. Epigenetics Chromatin 7(1), 6 (2014).
- 6 . Gene-induced embryological modifications of primordial germ cells in the mouse. J. Exp. Zool. 134(2), 207–237 (1957).
- 7 . Proliferation and migration of primordial germ-cells during compensatory growth in mouse embryos. J. Embryol. Exp. Morph. 64, 133–147 (1981).
- 8 Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev. 19(7), 815–826 (2005).
- 9 . Gene expression dynamics during germline specification in mice identified by quantitative single-cell gene expression profiling. Biol. Repro. 75(5), 705–716 (2006).
- 10 Cellular dynamics associated with the genome-wide epigenetic reprogramming in migrating primordial germ cells in mice. Development 134(14), 2627–2638 (2007).
- 11 . Extensive and orderly reprogramming of genome-wide chromatin modifications associated with specification and early development of germ cells in mice. Dev. Biol. 278(2), 440–458 (2005).
- 12 Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature 452(7189), 877–881 (2008).
- 13 The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol. Cell 48(6), 849–862 (2012).•• Used whole genome bisulfite sequencing and RNA-seq to identify dynamics of DNA methylation reprogramming in mouse PGCs.
- 14 Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells. Nat. Cell. Biol. 8(6), 623–630 (2006).
- 15 . Replication-coupled passive DNA demethylation for the erasure of genome imprints in mice. EMBO J. 32(3), 340–353 (2013).
- 16 . Polycomb group protein-associated chromatin is reproduced in post-mitotic G1 phase and is required for S phase progression. J. Biol. Chem. 283(27), 18905–18915 (2008).
- 17 . Parallel mechanisms of epigenetic reprogramming in the germline. Trends Genet. 28(4), 164–174 (2012).
- 18 . Fine-tuning evolution: germ-line epigenetics and inheritance. Reproduction 146(1), R37–R48 (2013).
- 19 . Post-natal imprinting: evidence from marsupials. Heredity 113(2), 145–155 (2014).
- 20 . Resourceful imprinting. Nature 432(7013), 53–57 (2004).
- 21 . Genomic imprinting in mammals: its life cycle, molecular mechanisms and reprogramming. Cell Res. 21(3), 466–473 (2011).
- 22 . Mammalian genomic imprinting. Cold Spring Harb. Perspect. Biol. 3(7), pii:a002592 (2011).
- 23 . Genomic imprinting, growth control and the allocation of nutritional resources: consequences for postnatal life. Curr. Opin. Endocrinol. Diabetes Obes. 14(1), 3–12 (2007).
- 24 Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 429(6994), 900–903 (2004).
- 25 Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse. Hum. Mol. Genet. 16(19), 2272–2280 (2007).
- 26 . Windows for sex-specific methylation marked by DNA methyltransferase expression profiles in mouse germ cells. Dev. Biol. 268(2), 403–415 (2004).
- 27 . Co-expression of de novo DNA methyltransferases Dnmt3a2 and Dnmt3L in gonocytes of mouse embryos. Gene Expr. Patterns 5(2), 231–237 (2004).
- 28 Sex-specific promoters regulate Dnmt3L expression in mouse germ cells. Hum. Reprod. 22(2), 457–467 (2007).
- 29 Meiotic and epigenetic defects in Dnmt3L-knockout mouse spermatogenesis. Proc. Natl Acad. Sci. USA 102(11), 4068–4073 (2005).
- 30 . Male germ cell differentiation involves complex repression of the regulatory network controlling pluripotency. FASEB J. 24(8), 3026–3035 (2010).
- 31 . Dnmt3L and the establishment of maternal genomic imprints. Science 294(5551), 2536–2539 (2001).
- 32 . Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 129(8), 1983–1993 (2002).
- 33 . Coordinate regulation of DNA methyltransferase expression during oogenesis. BMC Dev. Biol. 7, 36 (2007).
- 34 . A set of genes critical to development is epigenetically poised in mouse germ cells from fetal stages through completion of meiosis. Proc. Natl Acad. Sci. USA 110(40), 16061–16066 (2013).•• Performed ChIP-seq and RNA-seq analysis on male and female germ cells during embryogenesis and identified a set of developmentally critical epigenetically poised genes.
- 35 . Epigenetic transitions in germ cell development and meiosis. Dev. Cell 19(5), 675–686 (2010).
- 36 . Distinctive chromatin in human sperm packages genes for embryo development. Nature 460(7254), 473–478 (2009).
- 37 Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nat. Struct. Mol. Biol. 17(6), 679–687 (2010).
- 38 Molecular determinants of nucleosome retention at CpG-rich sequences in mouse spermatozoa. Nat. Struct. Mol. Biol. 20(7), 868–875 (2013).•• Analyzed the location of nucleosome retention in mouse spermatozoa, supporting the hypothesis for nucleosomal epigenetic inheritance.
- 39 Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Nat. Genet. 43(8), 811–814 (2011).•• High-throughput bisulfite analysis of mouse oocytes, sperm and preimplantation embryos.
- 40 . Technical considerations for reduced representation bisulfite sequencing with multiplexed libraries. J. Biomed. Biotechnol. 2012, 741542 (2012).
- 41 Stella is a maternal effect gene required for normal early development in mice. Curr. Biol. 13(23), 2110–2117 (2003).
- 42 A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. Dev. Cell 15(4), 547–557 (2008).
- 43 . Trim28 is required for epigenetic stability during mouse oocyte to embryo transition. Science 335(6075), 1499–1502 (2012).
- 44 . Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development 99(3), 371–382 (1987).
- 45 . Methylation levels of maternal and paternal genomes during preimplantation development. Development 113(1), 119–127 (1991).
- 46 Asymmetry in histone H3 variants and lysine methylation between paternal and maternal chromatin of the early mouse zygote. Mech. Dev. 122(9), 1008–1022 (2005).
- 47 . Demethylation of the zygotic paternal genome. Nature 403(6769), 501–502 (2000).
- 48 Active demethylation of the paternal genome in the mouse zygote. Curr. Biol. 10(8), 475–478 (2000).
- 49 . Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev. Biol. 241(1), 172–182 (2002).
- 50 5-hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat. Commun. 2, 241 (2011).
- 51 . Persistence of cytosine methylation of DNA following fertilisation in the mouse. PLoS ONE 7(1), e30687 (2012).
- 52 . Transient depletion of xDnmt1 leads to premature gene activation in Xenopus embryos. Genes Dev. 14(3), 313–327 (2000).
- 53 Non-conservation of mammalian preimplantation methylation dynamics. Curr. Biol. 14(7), R266–R267 (2004).
- 54 . Absence of genome-wide changes in DNA methylation during development of the zebrafish. Nat. Genet. 23(2), 139–140 (1999).
- 55 A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature 484(7394), 339–344 (2012).•• High-throughput DNA methylation analysis of mouse gametes and from zygote to postimplantation.
- 56 DNA methylation dynamics of the human preimplantation embryo. Nature 511(7511), 611–615 (2014).
- 57 . Replication-dependent loss of 5-hydroxymethylcytosine in mouse preimplantation embryos. Science 334(6053), 194 (2011).
- 58 Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324(5929), 930–935 (2009).
- 59 Targets and dynamics of promoter DNA methylation during early mouse development. Nat. Genet. 42(12), 1093–1100 (2010).
- 60 PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos. Nature 486(7403), 415–419 (2012).• Demonstrated that STELLA binds H3K9me2 to protect CpG sites against TET demethylation.
- 61 . Should I stay or should I go: protection and maintenance of DNA methylation at imprinted genes. Epigenetics 7(9), 969–975 (2012).
- 62 PGC7/Stella protects against DNA demethylation in early embryogenesis. Nat. Cell Biol. 9(1), 64–71 (2007).
- 63 Dynamics of Dnmt1 methyltransferase expression and intracellular localization during oogenesis and preimplantation development. Dev. Biol. 245(2), 304–314 (2002).
- 64 In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions. Mol. Cell 44(3), 361–372 (2011).
- 65 Zinc finger protein ZFP57 requires its co-factor to recruit DNA methyltransferases and maintains DNA methylation imprint in embryonic stem cells via its transcriptional repression domain. J. Biol. Chem. 287(3), 2107–2118 (2012).
- 66 Maintenance of genomic methylation patterns during preimplantation development requires the somatic form of DNA methyltransferase 1. Dev. Biol. 313(1), 335–346 (2008).
- 67 . Preimplantation expression of the somatic form of Dnmt1 suggests a role in the inheritance of genomic imprints. BMC Dev. Biol. 8, 9 (2008).
- 68 Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat. Genet. 40(8), 949–951 (2008).
- 69 . Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 308(5959), 548–550 (1984).
- 70 . Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37(1), 179–183 (1984).
- 71 . Inviability of parthenogenones is determined by pronuclei, not egg cytoplasm. Nature 310(5972), 66–67 (1984).
- 72 . Noncomplementation phenomena and their bearing on nondisjunctional effects. Basic Life Sci. 36, 363–376 (1985).
- 73 . Role for DNA methylation in genomic imprinting. Nature 366(6453), 362–365 (1993).
- 74 . Specification of germ cell fate in mice. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 358(1436), 1363–1370 (2003).
- 75 . Acquisition of the H19 methylation imprint occurs differentially on the parental alleles during spermatogenesis. Genomics 58(1), 18–28 (1999).
- 76 . The H19 methylation imprint is erased and re-established differentially on the parental alleles during male germ cell development. Hum. Mol. Genet. 9(19), 2885–2894 (2000).
- 77 . Timing of establishment of paternal methylation imprints in the mouse. Genomics 84(6), 952–960 (2004).
- 78 . Gene-specific timing and epigenetic memory in oocyte imprinting. Hum. Mol. Genet. 13(8), 839–849 (2004).
- 79 . Transcription and histone methylation changes correlate with imprint acquisition in male germ cells. EMBO J. 31(3), 606–615 (2012).
- 80 Transcription is required for establishment of germline methylation marks at imprinted genes. Genes Dev. 23(1), 105–117 (2009).
- 81 . Transcription is required to establish maternal imprinting at the Prader-Willi syndrome and Angelman syndrome locus. PLoS Genet. 7(12), e1002422 (2011).
- 82 Initial sequencing and analysis of the human genome. Nature 409(6822), 860–921 (2001).
- 83 . Transposable elements and the epigenetic regulation of the genome. Nat. Rev. Genet. 8(4), 272–285 (2007).
- 84 Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 35(2), 88–93 (2003).
- 85 Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science 339(6118), 448–452 (2013).
- 86 . Global profiling of DNA methylation erasure in mouse primordial germ cells. Genome Res. 22(4), 633–641 (2012).
- 87 Retrotransposons regulate host genes in mouse oocytes and preimplantation embryos. Dev. Cell 7(4), 597–606 (2004).
- 88 . Alu repeated DNAs are differentially methylated in primate germ cells. Nucleic Acids Res. 22(23), 5121–5127 (1994).
- 89 . Sex-linked dosage-sensitive modifiers as imprinting genes. Development 108(Suppl.), 107–113 (1990).
- 90 . Methylation and imprinting: from host defense to gene regulation? Science 260(5106), 309–310 (1993).
- 91 . Transposable elements: possible catalysts of organismic evolution. Trends Ecol. Evol. 10(3), 123–126 (1995).
- 92 . Imprinting and the initiation of gene silencing in the germ line. Cell 93(3), 309–312 (1998).
- 93 . Transgene silencing by the host genome defense: implications for the evolution of epigenetic control mechanisms in plants and vertebrates. Plant Mol. Biol. 43(2), 401–415 (2000).
- 94 . Host defenses to transposable elements and the evolution of genomic imprinting. Cytogenet. Genome Res. 110(1–4), 242–249 (2005).
- 95 . Imprinting mechanisms. Genome Res. 8(9), 881–900 (1998).
- 96 . Genomic imprinting: parental influence on the genome. Nat. Rev. Genet. 2(1), 21–32 (2001).
- 97 . Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat. Rev. Genet. 13(3), 153–162 (2012).
- 98 An unbiased assessment of the role of imprinted genes in an intergenerational model of developmental programming. PLoS Genet. 8(4), 41–53 (2012).
- 99 piRNAs can trigger a multigenerational epigenetic memory in the germline of C. elegans. Cell 150(1), 88–99 (2012).
- 100 piRNAs initiate an epigenetic memory of nonself RNA in the C. elegans germline. Cell 150(1), 65–77 (2012).
- 101 Function, targets, and evolution of Caenorhabditis elegans piRNAs. Science 337(6094), 574–578 (2012).
- 102 Conservation and expression of PIWI-interacting RNA pathway genes in male and female adult gonad of amniotes. Biol. Reprod. 89(6), 136 (2013).
- 103 . Small RNAs as guardians of the genome. Cell 136(4), 656–668 (2009).
- 104 . C. elegans piRNAs mediate the genome-wide surveillance of germline transcripts. Cell 150(1), 78–87 (2012).
- 105 . Transgenerational epigenetic inheritance: how important is it? Nat. Rev. Genet. 14(3), 228–235 (2013).
- 106 . Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science 286(5442), 1155–1158 (1999).
- 107 . Maternal care, gene expression, and the development of individual differences in stress reactivity. Ann. NY Acad. Sci. 896, 66–84 (1999).
- 108 . Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 12(11), 949–957 (1998).
- 109 . Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol. Cell. Biol. 23(15), 5293–5300 (2003).
- 110 . Germ-line epigenetic modification of the murine A vy allele by nutritional supplementation. Proc. Natl Acad. Sci. USA 103(46), 17308–17312 (2006).
- 111 . The penetrance of an epigenetic trait in mice is progressively yet reversibly increased by selection and environment. Proc. Biol. Sci. 279(1737), 2347–2353 (2012).
- 112 . Diet-induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female. FASEB J. 21(12), 3380–3385 (2007).
- 113 . Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet. 23(3), 314–318 (1999).
- 114 . Transposable elements in the mammalian germline: a comfortable niche or a deadly trap? Heredity 105(1), 92–104 (2010).
- 115 . Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice. PLoS Genet. 2(4), e49 (2006).
- 116 Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 155(1), 81–93 (2013).•• Showed transgenerational epigenetic effects using embryo transfer experiments.
- 117 Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat. Neurosci. 17(5), 667–669 (2014).
- 118 . Function and information content of DNA methylation. Nature 517(7534), 321–326 (2015).
- 119 . Maternal high-fat diet promotes body length increases and insulin insensitivity in second-generation mice. Endocrinology 150(11), 4999–5009 (2009).
- 120 Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143(7), 1084–1096 (2010).
- 121 . Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467(7318), 963–966 (2010).
- 122 . Male-line transgenerational responses in humans. Hum. Fertil. (Camb) 13(4), 268–271 (2010).
- 123 Intergenerational transmission of glucose intolerance and obesity by in utero undernutrition in mice. Diabetes 58(2), 460–468 (2009).
- 124 Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals. Proc. Natl Acad. Sci. USA 111(5), 1873–1878 (2014).
- 125 . Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS ONE 5(9), e13100 (2010).
- 126 In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345(6198), 1255903 (2014).
- 127 . Maternal high-fat diet effects on third-generation female body size via the paternal lineage. Endocrinology 152(6), 2228–2236 (2011).
- 128 Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes. Nat. Commun. 4, 2889 (2013).
- 129 Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc. Natl Acad. Sci. USA 94(7), 3290–3295 (1997).
- 130 Modifiers of epigenetic reprogramming show paternal effects in the mouse. Nat. Genet. 39(5), 614–622 (2007).
- 131 . Amplification of siRNA in Caenorhabditis elegans generates a transgenerational sequence-targeted histone H3 lysine 9 methylation footprint. Nat. Genet. 44(2), 157–164 (2012).
- 132 A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality. Nature 489(7416) 447–451 (2012).
- 133 . Transgenerational epigenetic effects. Annu. Rev. Genomics Hum. Genet. 9, 233–257 (2008).
- 134 . Transgenerational epigenetic inheritance: more questions than answers. Genome Res. 20(12), 1623–1628 (2010).
- 135 . Evolution. The Modern Synthesis. Allen & Unwin, London (1942).
- 136 . The Growth of Biological Thought: Diversity, Evolution, and Inheritance. Harvard University Press, USA (1982).
- 137 . Imprinted gene expression in hybrids: perturbed mechanisms and evolutionary implications. Heredity 113(2), 167–175 (2014).
- 138 . Epigenetic Inheritance and Evolution: The Lamarckian Dimension. Oxford University Press, UK, p360 (1995).
- 139 . The evolution of information in the major transitions. J. Theor. Biol. 239(2), 236–246 (2006).
- 140 . Soft inheritance: challenging the modern synthesis. Genet. Mol. Biol. 31(2), 389–395 (2008).• Summarizes the assumptions of the Modern Synthesis model for evolution and discusses the need for expansion to incorporate soft inheritance.
- 141 . Epigenetics for ecologists. Ecol. Lett. 11(2), 106–115 (2008).
- 142 . Evolution, the Extended Synthesis. MIT Press, Cambridge, USA (2010).
- 143 . A role for epigenetic inheritance in modern evolutionary theory? A comment in response to Dickins and Rahman. Proc. Biol. Sci. 280(1771), 20130903; 20131820 (2013).
- 144 Maternal obesity and diabetes induces latent metabolic defects and widespread epigenetic changes in isogenic mice. Epigenetics 8(6), 602–611 (2013).
- 145 . Neomorphic agouti mutations in obese yellow mice. Nat. Genet. 8(1), 59–65 (1994).
- 146 . Plasticity and robustness in development and evolution. Int. J. Epidemiol. 41(1), 219–223 (2012).
- 147 Regulation of supply and demand for maternal nutrients in mammals by imprinted genes. J. Physiol. 547(Pt 1), 35–44 (2003).
- 148 . Parent-specific gene expression and the triploid endosperm. Am. Nat. 134(1), 147–155 (1989).
- 149 . Genomic imprinting and kinship: how good is the evidence? Annu. Rev. Genet. 38(1), 553–585 (2004).
- 150 . A maternal–offspring coadaptation theory for the evolution of genomic imprinting. PLoS Biol. 4(12), e380 (2006).
- 151 . Epigenetics, brain evolution and behaviour. Front. Neuroendocrinol. 29(3), 398–412 (2008).