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Cited by 1,509Epigenetics and DNA MethylationGenomics and Chromatin DynamicsBirth, Development, and Health

Advances in epigenetics link genetics to the environment and disease

Open access
Cavalli, Giacomo, Heard, Edith·2019·Nature
DOI 10.1038/s41586-019-1411-0
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Abstract

Epigenetic research has accelerated rapidly in the twenty-first century, generating justified excitement and hope, but also a degree of hype. Here we review how the field has evolved over the last few decades and reflect on some of the recent advances that are changing our understanding of biology. We discuss the interplay between epigenetics and DNA sequence variation as well as the implications of epigenetics for cellular memory and plasticity. We consider the effects of the environment and both intergenerational and transgenerational epigenetic inheritance on biology, disease and evolution. Finally, we present some new frontiers in epigenetics with implications for human health.

AI snapshot

Written from the paper’s full text.

TL;DR

This review surveys how epigenetic mechanisms—DNA methylation, histone modifications, noncoding RNAs, and 3D chromatin organization—maintain gene activity states and mediate environmental influences, with implications for inheritance, disease, and aging. It argues that epigenetic inheritance is limited but real, especially in non-mammalian systems, and that the field is maturing toward clinical applications while cautioning against hype.

Key findings

  • Epigenetic inheritance can involve multiple cooperating layers, including heterochromatin, Polycomb/Trithorax complexes, DNA methylation, small RNAs, and topologically associating domains (TADs); these states are reversible and often require self-reinforcing loops or large chromatin domains. In fission yeast, RNAi-dependent heterochromatin supports stable inheritance, whereas H3K9me3 alone is insufficient unless the Epe1 demethylase is mutated.
  • Environmental and metabolic inputs can alter epigenomes. Examples include temperature-dependent sex determination in turtles involving KDM6B; heat effects on KDM6B and JARID2 splicing in bearded dragons; altered H3K9me3 and H3K27me3 across five generations in C. elegans exposed to bisphenol A; and changes in H3K27me3 and longevity inherited for at least two generations after a low-protein diet in Drosophila.
  • Transgenerational epigenetic inheritance in mammals is limited and debated. The mouse IAP insertion at the agouti locus is a classic example, but a systematic survey found multigenerational inheritance rare; the human Överkalix cohort links grandpaternal food supply to later mortality without molecular evidence; and a high-fat diet study up to the third generation found no heritable DNA methylome changes.
  • Disease and aging links include an epigenetic clock based on 353 CpG sites that correlates with age; epigenetic age accelerated by high BMI and reduced by education or physical activity; TAD disruption in 7.3% of congenital anomaly cases; and pancreatic cancer metastases showing large-scale chromatin reprogramming without obvious driver mutations, alongside frequent mutations in epigenetic regulators in cancer.

Methods

  • Narrative review, not primary research; it synthesizes literature across yeast, plants, C. elegans, Drosophila, mammals, and human cohorts.
  • Discusses mechanisms, inheritance, environmental epigenetics, disease, aging, and cancer, with boxes on epigenetic carriers and emerging technologies.
  • No systematic search, meta-analysis, original data collection, or statistical analysis is described.

Limitations

  • Stated: human environmental epigenetics faces confounding, multifactorial exposures, limited tissue access, and difficulty establishing causality between DNA sequence and epigenetic variation; direct links between environment, metabolism, and epigenetic components are urgently needed.
  • Stated: mammalian and human transgenerational inheritance is hard to study because maternal, seminal, in utero, and postnatal confounds cannot be excluded; some reported multigenerational effects have been criticized, and molecular evidence is lacking for the Överkalix cohort.
  • Evident: as a broad review, it does not perform systematic quality assessment or quantitative synthesis, and many cited findings come from model organisms and may not translate to humans.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41586-019-1411-0

Cites

163 of 163 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 141 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Maintenance of gene expression states often relies on many chromatin cofactors not specific to DNA sequence, which set up and maintain chromatin states across cell division and for long periods, sometimes without the original transcription factors.

    “The maintenance phase often involves a plethora of non-DNA sequence specific chromatin cofactors that set up and maintain chromatin states through cell division and for extended periods of time-sometimes in the absence of the initial transcription factors 3 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] 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). source

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  • Premisecitation

    The ability of a fertilized egg to produce many specialized cell types depends largely on coordinated action of hundreds of transcription factors that bind specific DNA sequences and activate or repress lineage genes.

    “The pluripotency of the initial cell and the establishment of cell types depend to a large extent on the coordinated deployment of hundreds of transcription factors that bind to specific DNA sequences to activate or repress the transcription of cell lineage genes 1 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Srivastava, D. & DeWitt, N. In vivo cellular reprogramming: the next generation. Cell 166, 1386–1396 (2016). source

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  • Premisecitation

    Because parental nucleosomes lack a precise replication process and many DNA-binding and chromatin components are lost during mitosis and meiosis, inheriting single nucleosome marks is especially difficult.

    “Owing to the lack of a precise 'replication' process for parental nucleosomes and to the loss of many DNA-binding factors and chromatin-associated components during mitosis and meiosis, the inheritance of single nucleosome marks poses specific challenges 28 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Reinberg, D. & Vales, L. D. Chromatin domains rich in inheritance. Science 361, 33–34 (2018). source

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  • Premisecitation

    Mathematical modelling and biological evidence indicate that chromatin heritability needs domains of several to hundreds of kilobases.

    “Mathematical modelling and biological evidence suggest that chromatin heritability requires the establishment of domains of several or even hundreds of kilobases in size [45][46][47] .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [45] Hathaway, N. A. et al. Dynamics and memory of heterochromatin in living cells. Cell 149, 1447–1460 (2012). source

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    • cites [46] Jost, D. & Vaillant, C. Epigenomics in 3D: importance of long-range spreading and specific interactions in epigenomic maintenance. Nucleic Acids Res. 46, 2252–2264 (2018). source

      Not checked in the free run.

    • cites [47] Yu, R., Wang, X. & Moazed, D. Epigenetic inheritance mediated by coupling of RNAi and histone H3K9 methylation. Nature 558, 615–619 (2018). The functional study of a genomic locus of Schizosaccharomyces pombe shows that a positive feedback loop involving the collaboration of RNAi and heterochromatin can maintain stable epigenetic inheritance through mitosis and meiosis, whereas inheritance is lost in the absence of RNAi inheritance because of the action of an H3K9me3-specific demethylase. source

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  • Interpretationnone given

    For epigenetic marks to be inherited through cell division, they must survive DNA replication and mitosis.

    “Furthermore, the inheritance of epigenetic marks through cell division requires that they survive DNA replication and mitosis (Fig. 2).”
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    Premisecitation

    DNA methylation was an early proposed carrier of epigenetic information, and later work showed chromatin proteins and noncoding RNAs also matter.

    “DNA methylation was proposed early on as a carrier of epigenetic information with subsequent work revealing that chromatin proteins and noncoding RNAs are also important for this process [10][11][12][13][14] .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001). source

      Not checked in the free run.

    • cites [11] Festuccia, N., Gonzalez, I., Owens, N. & Navarro, P. Mitotic bookmarking in development and stem cells. Development 144, 3633–3645 (2017). source

      Not checked in the free run.

    • cites [12] 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). source

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    Premisecitation

    Mutation rates differ across genome regions, life-cycle stages and diseases such as cancer, where they depend on cell of origin, environmental exposure and cancer type.

    “Mutation rates vary in different parts of the genome, at different stages of the life cycle and in diseases such as cancer, where they depend on the cell of origin, environmental exposure and cancer type [60][61][62] .”
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    • cites [60] Hama, N. et al. Epigenetic landscape influences the liver cancer genome architecture. Nat. Commun. 9, 1643 (2018). source

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    • cites [61] Polak, P. et al. Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature 518, 360–364 (2015). source

      Not checked in the free run.

    • cites [62] Supek, F. & Lehner, B. Clustered mutation signatures reveal that error-prone DNA repair targets mutations to active genes. Cell 170, 534–547.e523 (2017). source

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    Premisecitation

    In Drosophila, losing target DNA elements causes loss of PcG proteins and gene silencing within a few cell divisions, but sequence-independent silencing propagation can persist in mammalian cell culture.

    “Loss of the target DNA sequence elements results in loss of PcG proteins and of gene silencing within a few cell divisions in Drosophila 35,36 , although sequence-independent propagation of silencing can be maintained in mammalian cell culture 37 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [35] 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). source

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    • cites [36] Laprell, F., Finkl, K. & Müller, J. Propagation of Polycomb-repressed chromatin requires sequence-specific recruitment to DNA. Science 356, 85–88 (2017). source

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    • cites [37] Moussa, H. F. et al. Canonical PRC1 controls sequence-independent propagation of Polycomb-mediated gene silencing. Nat. Commun. 10, 1931 (2019). source

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    Premisecitation

    Nucleosomes are continually remodelled, histones are exchanged, and all DNA and histone marks found so far can be reversed, though exchange and stability rates differ by genomic region.

    “Indeed, nucleosomes are subject to constant remodelling, histones are exchanged and all DNA and histone marks discovered so far are reversible, although the rates of exchange and the stability of the marks vary in different genomic domains 27 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Allis, C. D. & Jenuwein, T. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 17, 487–500 (2016). source

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    Premisecitation

    Chromatin states can affect transcription factor binding, and DNA sequence polymorphisms can affect chromatin states.

    “Chromatin states can influence transcription factor binding 54 , and DNA sequence polymorphism influences chromatin states.”
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    • cites [54] Deplancke, B., Alpern, D. & Gardeux, V. The genetics of transcription factor DNA binding variation. Cell 166, 538–554 (2016). source

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    Premisecitation

    An analysis of chromatin accessibility and CTCF binding in parents and children from families of different ancestry found many bound sites unique to each ancestry, with differential binding mainly explained by genetic variation.

    “For example, analysis of chromatin accessibility and 'CCCTC-binding factor' (CTCF) DNA binding in parents and children from families with different ancestry found a substantial percentage of bound sites that were unique to each ancestry, with differential binding being explained mainly by genetic variation 56 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] McDaniell, R. et al. Heritable individual-specific and allele-specific chromatin signatures in humans. Science 328, 235–239 (2010). source

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    Premisecitation

    DNA methylation and nucleosome positioning can influence mutation rates.

    “Mutation rates can be affected by DNA methylation 63 and nucleosome positioning 64 .”
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    • cites [63] Poulos, R. C., Olivier, J. & Wong, J. W. H. The interaction between cytosine methylation and processes of DNA replication and repair shape the mutational landscape of cancer genomes. Nucleic Acids Res. 45, 7786–7795 (2017). source

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    • cites [64] Pich, O. et al. Somatic and germline mutation periodicity follow the orientation of the DNA minor groove around nucleosomes. Cell 175, 1074–1087.e1018 (2018). source

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    Premisecitation

    Hypermutation of the heterochromatic inactive X chromosome has been observed in cancer and may result from DNA replication stress in aberrantly proliferating cells.

    “Hypermutation of the heterochromatic inactive X chromosome has also been noted in cancer and may be due to DNA replication stress in aberrantly proliferating cells 67 .”
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    • cites [67] Jäger, N. et al. Hypermutation of the inactive X chromosome is a frequent event in cancer. Cell 155, 567–581 (2013). source

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    Premisecitation

    Mutations in histone and DNA methyltransferases, demethylases, chromatin remodellers and other chromatin factors including histones are common in disease, and their effects may be targeted therapeutically.

    “On the other hand, mutations that affect histone and DNA methyltransferases, or demethylases (TET enzymes), chromatin remodellers and other chromatin factors including histones, are frequently found in disease 57 and their effects may be specifically targeted by therapeutic interventions 58 .”
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    • cites [57] Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 174, 1034–1035 (2018). source

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    • cites [58] Mohammad, F. et al. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nat. Med. 23, 483–492 (2017). source

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    Interpretationcitation

    The relationship between DNA sequence and epigenetic changes is often cryptic, so mutations can be missed or mistaken for epimutations, causing misconceptions about whether epigenetic changes drive or merely accompany disease.

    “The often cryptic relationship between DNA sequence and epigenetic changes can mean that mutations may be overlooked or mistaken for epimutations, leading to misconceptions about the driver versus passenger role for epigenetic changes 59 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Lappalainen, T. & Greally, J. M. Associating cellular epigenetic models with human phenotypes. Nat. Rev. Genet. 18, 441–451 (2017). source

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    Premisecitation

    Parental H3 and H4 histones are deposited near their pre-replication positions and, after replication, are distributed roughly equally to leading and lagging daughter DNA strands by dedicated complexes.

    “Deposition of parental H3 and H4 histones occurs within few hundred base pairs of their pre-replication position and, upon replication, they are roughly equally distributed to the leading and the lagging strand daughter DNA molecules, through the action of dedicated molecular complexes 29,30 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [29] Yu, C. et al. A mechanism for preventing asymmetric histone segregation onto replicating DNA strands. Science 361, 1386–1389 (2018). source

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    • cites [30] Petryk, N. et al. MCM2 promotes symmetric inheritance of modified histones during DNA replication. Science 361, 1389–1392 (2018). source

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    Premisecitation

    Metabolic changes can affect specific loci and produce long-lasting epigenetic modifications, including intergenerational epigenetic inheritance.

    “On the other hand, metabolic changes can affect specific loci and induce long-lasting epigenetic modifications, including intergenerational epigenetic inheritance [85][86][87] .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [85] Lu, T. T. et al. The Polycomb-dependent epigenome controls β cell dysfunction, dedifferentiation, and diabetes. Cell Metab. 27, 1294–1308.e7 (2018). source

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    • cites [86] Öst, A. et al. Paternal diet defines offspring chromatin state and intergenerational obesity. Cell 159, 1352–1364 (2014). source

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    • cites [87] Sharma, U. et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351, 391–396 (2016). source

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  • May combine two claims.

    Interpretationreasoning

    Temperature affects PRC2 factors in diverse animal and plant species, suggesting that temperature sensing by PRC2 might be evolutionarily conserved, though other environmental effects can also stably modify chromatin.

    “It is intriguing that temperature affects PRC2 factors in diverse animal and plant species, suggesting that temperature sensing by PRC2 might be evolutionarily conserved, although this is not the only environmental effect that can stably modify chromatin.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Confounding effects, multifactorial exposure, tissue access, and assessment of causality for DNA sequence versus epigenetic variation remain major challenges, especially in humans.

    “However, confounding effects, the impact of multifactorial exposure, access to appropriate tissues and assessment of causality for DNA sequence versus epigenetic variation remain major challenges, particularly in humans.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In Tetrahymena, transgenerational epigenetic inheritance participates in programmed DNA elimination from the somatic nucleus and involves small RNA-dependent heterochromatin formation on the DNA elements to be eliminated.

    “In Tetrahymena, TEI participates in the phenomenon called 'programmed DNA elimination' from the transcriptionally active somatic nucleus and, again, it involves small RNA-dependent formation of heterochromatin on the DNA elements to be eliminated 103 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Noto, T. & Mochizuki, K. Small RNA-mediated trans-nuclear and trans-element communications in Tetrahymena DNA elimination. Curr. Biol. 28, 1938–1949.e1935 (2018). source

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    Premisecitation

    The modern evolutionary synthesis postulates that evolution acts mainly through natural selection on phenotypes, ultimately affecting DNA sequences.

    “The modern evolutionary synthesis 93 postulates that evolution acts mainly via natural selection on phenotypes, ultimately affecting DNA sequences.”
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    • cites [93] Huxley, J. S. Evolution: the Modern Synthesis (Allen and Unwin, 1942).

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    Premisecitation

    piRNAs are inherited maternally and can be amplified by a ping-pong system, helping the organism resist new invasions and adapt its genome to them.

    “piRNAs are maternally heritable and can be amplified via a ping-pong system, effectively allowing the organism to resist new invasions and adapt their genome to them 69 .”
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    • cites [69] Grentzinger, T. et al. piRNA-mediated transgenerational inheritance of an acquired trait. Genome Res. 22, 1877–1888 (2012). source

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    Premisecitation

    In the carpenter ant Camponotus floridanus, the balance between morphologically distinct worker castes depends on histone acetylation levels, which may be influenced by feeding behaviour.

    “Another form of environmentally induced chromatin regulation is found in social insects such as the carpenter ant Camponotus floridanus, in which the balance between morphologically distinct worker castes depends on the levels of histone acetylation, which may be influenced by feeding behaviour 82 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Simola, D. F. et al. Epigenetic (re)programming of caste-specific behavior in the ant Camponotus floridanus. Science 351, aac6633 (2016). source

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  • May combine two claims.

    Premisecitation

    Histone demethylases KDM5A and KDM6A sense oxygen concentrations and modulate H3K4me3 and H3K27me3 levels.

    “The recent discovery that histone demethylases KDM5A and KDM6A (also known as UTX) can sense oxygen concentrations and thereby modulate H3K4me3 and H3K27me3 levels 91,92 is a first step in this direction.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [91] Batie, M. et al. Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science 363, 1222–1226 (2019). source

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    • cites [92] Chakraborty, A. A. et al. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science 363, 1217–1222 (2019). source

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    Premisecitation

    This KZFP-ERV strategy allows rapid evolution of gene regulation through KZFP binding to ERVs near genes, affecting gene expression dynamics and levels.

    “This strategy also enables the rapid evolution of gene regulation strategies via binding of KZFP to ERVs near genes 72 , thus influencing gene expression dynamics and levels.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Imbeault, M., Helleboid, P. Y. & Trono, D. KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks. Nature 543, 550–554 (2017). Analysis of KZFPs shows that most of them bind to transposable elements and that, in addition to their silencing, they exploit some of their evolutionarily conserved DNA fragments as gene regulatory platforms even in transposable element copies that have lost all transposition potential. source

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    Premisecitation

    Transposons can affect gene activity in several ways, including as regulatory elements or by interfering with transcription.

    “We now know that transposons can influence gene activity in multiple ways, acting as regulatory elements or interfering with transcription 68 .”
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    • cites [68] Shapiro, J. A. Exploring the read-write genome: mobile DNA and mammalian adaptation. Crit. Rev. Biochem. Mol. Biol. 52, 1–17 (2017). source

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    Premisecitation

    Plants make small RNAs from double-stranded precursors using dedicated polymerases; these RNAs target DNA methylation and H3K9 methylation machinery.

    “Plants produce small RNAs derived from double-stranded precursors, which are synthesized by dedicated polymerases and target DNA methylation and the H3K9 methylation machinery 71 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Wendte, J. M. & Pikaard, C. S. The RNAs of RNA-directed DNA methylation. Biochim. Biophys. Acta. Gene Regul. Mech. 1860, 140–148 (2017). source

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  • May combine two claims.

    Premisenone given

    In mammals, KAP1/TRIM28 represses endogenous retroviruses and co-recruits heterochromatin proteins such as SETDB1 by interacting with KRAB domain-containing zinc-finger proteins.

    “Finally, numerous strategies are deployed in mammals, the most recently characterized being the repression of endogenous retroviruses (ERVs) by the KAP1 protein (also known as TRIM28), which co-recruits heterochromatin proteins such as SETDB1 by interacting with Krüppel-associated box (KRAB) domain-containing zinc-finger proteins (KZFPs).”
    Quote in the paperNot a substantial claim

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    Premisecitation

    The role of epigenetics in environmental responses is well established in plants, especially Polycomb-based vernalization, and similar processes appear to occur in some animals.

    “The importance of epigenetics in environmental responses is well-established in plants, particularly in Polycomb-based vernalization 73 , but similar processes appear to take place in some animal species.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Friedrich, T., Faivre, L., Bäurle, I. & Schubert, D. Chromatin-based mechanisms of temperature memory in plants. Plant Cell Environ. 42, 762–770 (2019). source

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  • May combine two claims.

    Premisecitation

    Epigenetic age is accelerated by high body mass index and reduced by high education or physical activity, low body mass index, and consumption of fish, poultry, fruits and vegetables.

    “Furthermore, epigenetic age is adversely affected (accelerated) by a high body mass index, whereas it is reduced by high levels of education or physical activity, a low body mass index and consumption of fish, poultry, fruits and vegetables 128 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Quach, A. et al. Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging 9, 419–446 (2017). source

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    Premisecitation

    Changes in DNA methylation, histone modifications, and non-coding RNA function are common in disease, as are mutations in epigenetic components.

    “Changes in the levels of DNA methylation, histone modifications and changes in non-coding RNA (ncRNA) function are common in disease, as are mutations in epigenetic components 57,125 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [57] Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 174, 1034–1035 (2018). source

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    • cites [125] De Rubeis, S. et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209–215 (2014). Analysis of exome sequencing data from a large cohort of individuals with autism and control participants identifies a set of genes likely to affect risk, including those involved in synapse formation, transcriptional regulation and chromatin remodelling pathways. source

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    Premisecitation

    Adolescence is a third susceptibility window during which adverse life experiences affect the risk of anxiety, depression and aggressive behaviour, associated with DNA methylation of specific genes or alterations in HDAC1 levels.

    “Behavioural molecular genetics has identified a third susceptibility window, adolescence, during which adverse life experiences affect the risk of anxiety, depression and aggressive behaviour, associated with DNA methylation of specific genes 138 or with alterations in levels of HDAC1 139 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [138] Gouin, J. P. et al. Associations among oxytocin receptor gene (OXTR) DNA methylation in adulthood, exposure to early life adversity, and childhood trajectories of anxiousness. Sci. Rep. 7, 7446 (2017).

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    • cites [139] Mitjans, M. et al. Violent aggression predicted by multiple pre-adult environmental hits. Mol. Psychiatry https://doi.org/10.1038/s41380-018-0043-3 (2018). source

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  • May combine two claims.

    Interpretationreasoning

    Transgenerational epigenetic inheritance is limited but possible in humans.

    “These studies suggest that TEI is limited but possible in humans.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Both heterochromatin and Polycomb can induce transgenerational epigenetic inheritance.

    “These data suggest that both heterochromatin and Polycomb can induce TEI.”
    Quote in the paperSubstantial claim

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    Premisecitation

    A recent report found that a high-fat diet induced insulin resistance, obesity and addictive-like behaviours up to the third generation but did not identify heritable changes in the DNA methylome.

    “However, a recent report in which a high-fat diet induced insulin resistance, obesity and addictive-like behaviours up to the third generation did not identify heritable changes in the DNA methylome 123 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] Sarker, G. et al. Transgenerational transmission of hedonic behaviors and metabolic phenotypes induced by maternal overnutrition. Transl. Psychiatry 8, 195 (2018). source

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    Premisecitation

    In most sexually reproducing organisms, the germline is separated from the soma, and Weismann postulated that information flows only from germ cells to the soma.

    “Unlike plants, the germline is separated from the soma in most sexually reproducing organisms, and Weismann postulated that information can flow only from germ cells to the soma 106 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [106] Weismann, A. The Germ-Plasm. A Theory of Heredity (Charles Scribner’s Sons, New York, 1893). source

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    Interpretationcitation

    Ageing may correlate with reduced plasticity in the expression of some bivalent genes, which might resolve into repressed or active states, and with active genes changing their expression levels.

    “Many of the 353 CpGs investigated are located close to poised promoters of bivalent genes (marked by H3K4me3 and H3K27me3), or to active promoters 126 , suggesting that ageing may correlate with reduced plasticity in the expression of some bivalent genes, which might resolve into repressed or active states, and with active genes changing their expression levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013). Analysis of a large panel of DNA methylation samples identifies an age predictor that correlates the methylation levels of a few hundred CpG sites with chronological age and is applicable to a large panel of tissues, and shows that cancer cells have accelerated ageing based on their DNA methylation levels. source

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    Interpretationreasoning

    Mutations in epigenetic components alter cell division, differentiation, adhesion and proliferation, increase gene expression heterogeneity, and thereby promote tumorigenesis.

    “These mutations alter cellular properties such as cell division, cell differentiation, adhesion and proliferation, and increase the heterogeneity of gene expression, thereby promoting tumorigenesis.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In humans, epidemiological evidence from the Överkalix cohort established links between grandpaternal food supply at the beginning of the twentieth century and the mortality rate of subsequent generations, although molecular evidence is unavailable for this cohort.

    “In humans, epidemiological evidence from the Överkalix population cohort established links between grandpaternal food supply at the beginning of the twentieth century and the mortality rate of subsequent generations 121 , although molecular evidence is unavailable for this cohort.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Pembrey, M., Saffery, R. & Bygren, L. O. Human transgenerational responses to early-life experience: potential impact on development, health and biomedical research. J. Med. Genet. 51, 563–572 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C. elegans epialleles involve heterochromatin components and may or may not involve piRNAs depending on the induction paradigm.

    “C. elegans epialleles (epigenetically modified alleles that induce specific phenotypes and are heritable over many generations) involve heterochromatin components (Fig. 3b), which, depending on the induction paradigm, may or may not involve piRNAs 79,107 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [79] Klosin, A., Casas, E., Hidalgo-Carcedo, C., Vavouri, T. & Lehner, B. Transgenerational transmission of environmental information in C. elegans. Science 356, 320–323 (2017). source

      Not checked in the free run.

    • cites [107] Ashe, A. et al. piRNAs can trigger a multigenerational epigenetic memory in the germline of C. elegans. Cell 150, 88–99 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In plants, transgenerational epigenetic inheritance is well described and plant epialleles can be stable over many generations.

    “In plants, TEI has also been well-described.Plant epialleles can be stable over many generations, and TEI is generally conveyed by RNA-directed DNA methylation (Fig. 3a)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [95] Heard, E. & Martienssen, R. A. Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157, 95–109 (2014). source

      Not checked in the free run.

    • cites [104] Teixeira, F. K. et al. A role for RNAi in the selective correction of DNA methylation defects. Science 323, 1600–1604 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Retroelements and some genes involved in neurological and metabolic disorders remain methylated during the wave of DNA demethylation in human primordial germ cells.

    “DNA methylation has been suggested as a potential mechanism for these effects, and retroelements and some genes involved in neurological and metabolic disorders remain methylated during the wave of DNA demethylation in human primordial germ cells 122 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Tang, W. W. et al. A unique gene regulatory network resets the human germline epigenome for development. Cell 161, 1453–1467 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These mutations include DNA methylases and demethylases, histones, histone modifiers, chromatin remodelling and chromosome architecture genes, and metabolic genes IDH1 and IDH2 that affect histone and DNA methylation and might perturb 3D genome architecture.

    “These include mutations in DNA methylases and demethylases, histones 144 and histone modifiers, and genes involved in chromatin remodelling and chromosome architecture, but also metabolic genes such as IDH1 and IDH2 that affect histone and DNA methylation 57 and might perturb 3D genome architecture 145 (Fig. 4b).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [57] Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 174, 1034–1035 (2018). source

      Not checked in the free run.

    • cites [145] Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114 (2016). Analysis of gliomas carrying mutation in IDH genes known to increase DNA methylation levels shows hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites that alters TAD boundaries and induces illegitimate oncogene activation. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Epigenetic mechanisms buffer environmental variation while allowing plastic responses to the most extreme environmental conditions.

    “Epigenetic mechanisms buffer environmental variation while allowing plastic responses to the most extreme environmental conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Low maternal care in mice decreases DNMT3a and DNA methylation at the L1 promoter and simultaneously induces mobilization of L1 elements in the hippocampus.

    “Interestingly, one study found that low maternal care in mice decreases DNMT3a and DNA methylation at the L1 promoter and simultaneously induces the mobilization of L1 elements in the hippocampus, suggesting that environmental variation can cause genetic and epigenetic changes simultaneously 142 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [142] Bedrosian, T. A., Quayle, C., Novaresi, N. & Gage, F. H. Early life experience drives structural variation of neural genomes in mice. Science 359, 1395–1399 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Analysis of pancreatic cancer metastases did not uncover obvious driver mutations; instead, large-scale chromatin reprogramming was observed with changes in H3K9me3 in many chromosomal domains.

    “Furthermore, analysis of pancreatic cancer metastases did not uncover any obvious driver mutations; instead, large-scale chromatin reprogramming was observed, with changes in the level of H3K9me3 in many chromosomal domains 149 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] McDonald, O. G. et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat. Genet. 49, 367–376 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Most organisms buffer environmental variation in physiology and inheritance, although buffering does not erase every bit of epigenetic information.

    “Most organisms buffer environmental variation in physiology and inheritance, although buffering does not erase every bit of epigenetic information (Fig. 5).”
    Quote in the paperNot a substantial claim
42 of 42

  • The paper relies on this without support.

    A large number of epigenome features are erased in germline cell chromatin before and during meiosis.

    “Furthermore, a large number of epigenome features are erased in germline cell chromatin before and during meiosis.”

  • The paper relies on this without support.

    Epigenetic alterations are more readily reversible than DNA mutations and can be targeted with increasing specificity.

    “and epigenetic alterations are more readily reversible than DNA mutations and can be targeted with increasing specificity.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Epigenetic regulation mediates direct epigenetic effects or gene-by-environment interactions and can lead to complex diseases.

    “Epigenetic regulation mediates direct epigenetic effects or gene-by-environment interactions and can lead to complex diseases.33,34”

    From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [34]

    The Environmental epigenetics section describes gene-by-environment interactions and epigenetic responses to environmental variation. Developmental epigenetics and disease says epigenetic components might mediate some effects of early environmental exposure on later disease risk. But Epigenetics, health and disease cautions that driver and passenger roles remain to be distinguished, so the claim overstates the established causal link to complex diseases. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

Research works printed but not linked: 7

  1. Waddington, C. H. The Epigenotype. Endeavour 1, 18–20 (1942).
  2. Holliday, R. & Pugh, J. E. DNA modification mechanisms and gene activity during development. Science 187, 226–232 (1975). · DOI
  3. Liu, X. et al. UHRF1 targets DNMT1 for DNA methylation through cooperative binding of hemi-methylated DNA and methylated H3K9. Nat. Commun. 4, 1563 (2013).
  4. Wu, P. et al. 3D genome of multiple myeloma reveals spatial genome disorganization associated with copy number variations. Nat. Commun. 8, 1937 (2017).
  5. Gouin, J. P. et al. Associations among oxytocin receptor gene (OXTR) DNA methylation in adulthood, exposure to early life adversity, and childhood trajectories of anxiousness. Sci. Rep. 7, 7446 (2017).
  6. Riggs, A. D., Martienssen, R. A. & Russo, V. E. A. in Epigenetic Mechanisms of Gene Regulation (ed. Russo, V. E. A., Martienssen, R. A. & Riggs, A. D.) 1–4 (Cold Spring Harbor Laboratory Press, 1996).
  7. Clark, S. J. et al. scNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells. Nat. Commun. 9, 781 (2018).

Cited by

Sorted by citations

Authors
Cavalli, G., & Heard, E.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
Cavalli, Giacomo
ORCID
Cavalli, Giacomo
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2019-07
Volume
571
Issue
7766
Pages
489-499
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-019-1411-0
OpenAlex
W2963537251
Cited by
1,509
References
163
Citations by year
2026: 127 · 2025: 249 · 2024: 269 · 2023: 209 · 2022: 213 · 2021: 218 · 2020: 201 · 2019: 21 · 2017: 1
FWCI
14.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Institut National de la Santé et de la Recherche Médicale
  • Centre National de la Recherche Scientifique
  • H2020 European Research Council (671027, 788972)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
Keywords
epigenetics, DNA sequence variation, cellular memory, cellular plasticity, intergenerational epigenetic inheritance, transgenerational epigenetic inheritance, environmental influences on gene expression, aging, disease, evolution, human health
MeSH terms
Aging, Animals, Chromatin, Disease, Humans, Neoplasms, Genetic Variation, DNA Methylation, Epigenesis, Genetic, Epigenomics, Gene-Environment Interaction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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