Review Article | Published:

Functions and mechanisms of epigenetic inheritance in animals

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


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

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

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

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

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

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

    • Ozren Bogdanović


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

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The authors declare no competing interests.

Corresponding authors

Correspondence to Nicola Iovino or Ozren Bogdanović.

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

Intergenerational epigenetic inheritance

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

Facultative heterochromatin

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

PIWI-interacting RNAs

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

Primordial germ cells

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

Imprinting control regions

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

Prader–Willi syndrome

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

Angelman syndrome

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

Bisulfite sequencing

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


Genetically identical alleles displaying distinct epigenetic modifications.


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

Microsatellite instability

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

Differentially methylated region

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

Ten-eleven translocation (TET) enzymes

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

CpG islands

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

Zygotic genome activation

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

Constitutive heterochromatin

Highly condensed, permanently transcriptionally silent late-replicating chromatin.


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

Homeotic transformation

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

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