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Understanding transgenerational epigenetic inheritance via the gametes in mammals

Key Points

  • Reprogramming of the epigenome in mammals occurs in both the germline and the early developing embryo. Some regions of the epigenome appear to escape this process.

  • Parentally imprinted genes are not reprogrammed during early development but are reprogrammed in the germline.

  • A small number of genes escape reprogramming at both stages. This includes some transgenes (that are made up of head-to-tail repeats) and some single-copy genes that are driven off repeated elements, such as retrotransposons.

  • The molecular nature of the molecules involved in this transgenerational epigenetic inheritance via the gametes is under investigation. The prevailing view has been that DNA methylation is the most likely candidate.

  • Here we suggest that RNA that is carried from the mature gametes to the zygote may be the molecule that carries this memory of transcriptional state across generations.


It is known that information that is not contained in the DNA sequence — epigenetic information — can be inherited from the parent to the offspring. However, many questions remain unanswered regarding the extent and mechanisms of such inheritance. In this Review, we consider the evidence for transgenerational epigenetic inheritance via the gametes, including cases of environmentally induced epigenetic changes. The molecular basis of this inheritance remains unclear, but recent evidence points towards diffusible factors, in particular RNA, rather than DNA methylation or chromatin. Interestingly, many cases of epigenetic inheritance seem to involve repeat sequences.

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Figure 1: Transgenerational epigenetic inheritance at transgenes and metastable epialleles.
Figure 2: Heat-shock-induced disruption of heterochromatin in Drosophila melanogaster.
Figure 3: Imprinting of the Rasgrf1 differentially methylated region via piRNA-directed DNA methylation.


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E.W. is a National Health and Medical Research Council (NHMRC) Australia Fellow. We thank N. Youngson for helpful discussions and M. Blewitt for critical reading of the manuscript.

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The portion of the genome that stays highly condensed throughout the cell cycle. It contains a high proportion of repetitive sequences, is gene-poor overall and is enriched for histone marks, such as histone H3 lysine 9 trimethylation (H3K9me3) and H4K20me3, as well as DNA methylation. Heterochromatin is generally associated with gene silencing.

Histone modifications

Covalent alterations of histone tail residues that can alter chromatin structure. Modifications include phosphorylation, methylation, acetylation, sumoylation and ubiquitylation.

Intracisternal A particle

(IAP). A long terminal repeat (LTR)-containing retrotransposon of mice that resembles a retrovirus but has a defective env gene.


An isoflavone found in plants that acts as an antioxidant and binds to the oestrogen receptor, hence its classification as a phytoestrogen.

Hypothalamic–pituitary–adrenal axis

(HPA axis). A set of interactions between the hypothalamus, the pituitary gland and the adrenal glands that control reactions to stress.

Glucocorticoid receptor

The receptor to which cortisol and other glucocorticoids bind. It is expressed throughout the body and controls transcription of many genes involved in development, metabolism and the immune response.


A neurogenic region of the forebrain that has important functions in learning and memory.


A fungicide used on vines, fruits and vegetables. It is associated with the development of testicular tumours. There is some evidence that it is carcinogenic and can act as an endrocrine disruptor.

Peroxisome proliferator-activated receptor alpha

(PPARα). A nuclear receptor and transcription factor involved in lipid metabolism.

Bisulphite sequencing

Treatment of DNA with sulphite ions increases the relative resistance of the conversion of methylcytosine to uracil compared with cytosine. PCR amplification and sequencing of the DNA following conversion shows a thymine where a cytosine was located, whereas persistence of a cytosine reflects its methylation in the starting DNA sample.


Mitotically heritable changes in epigenetic state but not gene sequence. Epimutation usually takes place by an abnormal increase or decrease in the methylation status of a gene. The heritability of epimutations across generations is currently under debate.


MutL homologue 1, colon cancer nonpolyposis type 2 (Escherichia coli) is a human gene coding for a protein that has an important role in DNA repair.


MutS homologue 2, colon cancer nonpolyposis type 2 (Escherichia coli) is another human gene coding for a protein involved in DNA repair.

Polycomb repressive complex 1

(PRC1). Silencing of the homeotic genes in development requires the Polycomb group proteins (PcGs). PcGs form two distinct multiprotein complexes, PRC1 and PRC2.


(miRNAs). Evolutionarily conserved small non-coding RNAs (~22-nucleotides long) that silence gene expression by degrading or inhibiting translation of mRNA transcripts in a sequence-specific manner.

Endogenous small interfering RNAs

(endo-siRNAs). Small RNAs that originate, in a Dicer-dependent manner, from long double-stranded (sense–antisense or hairpin) precursors. Initially mainly thought of as a mechanism of host defence against exogenous double-stranded RNA, endo-siRNAs are now known to also regulate endogenous mRNAs in mouse oocytes and Caenorhabditis elegans.

PIWI-interacting RNAs

(piRNAs). Small (24–31 bp) RNAs that are associated with PIWI-clade proteins of the Argonaute family. They ensure genome stability in the germline of flies, mice and zebrafish by silencing transposable and repetitive elements.

Position effect variegation

(PEV). This term describes a type of phenotypic variegation among cells of the same type that is the result of mosaic silencing of a particular gene. The variegation in these cases is due to the position of the gene adjacent to a heterochromatic region of the chromosome.

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

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