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A spontaneous genetically-induced epiallele at a retrotransposon shapes host genome function

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Cite this article as: eLife 2021;10:e65233 doi: 10.7554/eLife.65233

Abstract

Intracisternal A-particles (IAPs) are endogenous retroviruses (ERVs) responsible for most insertional mutations in the mouse. Full-length IAPs harbour genes flanked by long terminal repeats (LTRs). Here, we identify a solo LTR IAP variant (Iap5-1solo) recently formed in the inbred C57BL/6J mouse strain. In contrast to the C57BL/6J full-length IAP at this locus (Iap5-1full), Iap5-1solo lacks DNA methylation and H3K9 trimethylation. The distinct DNA methylation levels between the two alleles are established during preimplantation development, likely due to loss of KRAB zinc finger protein binding at the Iap5-1solo variant. Iap5-1solo methylation increases and becomes more variable in a hybrid genetic background yet is unresponsive to maternal dietary methyl supplementation. Differential epigenetic modification of the two variants is associated with metabolic differences and tissue-specific changes in adjacent gene expression. Our characterisation of Iap5-1 as a genetically-induced epiallele with functional consequences establishes a new model to study transposable element repression and host-element co-evolution.

Data availability

Sequencing data have been deposited in GenBank under accession number MW308129. GEO accession codes for publicly available ChIP-seq datasets analysed in this study are listed is Supplementary Table 5.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Tessa M Bertozzi

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2900-6740
  2. Nozomi Takahashi

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Geula Hanin

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Anastasiya Kazachenka

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Anne C Ferguson-Smith

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    afsmith@gen.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7608-5894

Funding

Wellcome Trust (210757/Z/18/Z)

  • Anne C Ferguson-Smith

Medical Research Council (MR/R009791/1)

  • Anne C Ferguson-Smith

Biotechnology and Biological Sciences Research Council (BB/R009996/1)

  • Anne C Ferguson-Smith

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Mouse work was carried out in accordance with the Animals (Scientific Procedures) Act 1986 Amendment Regulations 2012 following ethical review by the University of Cambridge Animal Welfare and Ethical Review Body (Home Office project license # PC213320E).

Reviewing Editor

  1. Deborah Bourc'his, Institut Curie, France

Publication history

  1. Received: November 27, 2020
  2. Accepted: March 22, 2021
  3. Accepted Manuscript published: March 23, 2021 (version 1)

Copyright

© 2021, Bertozzi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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