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Molecular mechanisms of transgenerational epigenetic inheritance

Nature Reviews Genetics volume 23, pages 325–341 (2022)Cite this article

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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.

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

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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).

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  1. Institute of Human Genetics, CNRS and University of Montpellier, Montpellier, France

    Maximilian H. Fitz-James & Giacomo Cavalli

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  1. Maximilian H. Fitz-James
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Correspondence to Giacomo Cavalli.

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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.

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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

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