Sequence features of retrotransposons allow for epigenetic variability

  1. Kevin R Costello
  2. Amy Leung
  3. Candi Trac
  4. Michael Lee
  5. Mudaser Basam
  6. J Andrew Popsilik
  7. Dustin E Schones  Is a corresponding author
  1. Beckman Research Institute, United States
  2. Van Andel Research Institute, United States

Abstract

Transposable elements (TEs) are mobile genetic elements that make up a large fraction of mammalian genomes. While select TEs have been co-opted in host genomes to have function, the majority of these elements are epigenetically silenced by DNA methylation in somatic cells. However, some TEs in mice, including the Intracisternal A-particle (IAP) subfamily of retrotransposons, have been shown to display interindividual variation in DNA methylation. Recent work has revealed that IAP sequence differences and strain-specific KRAB zinc finger proteins (KZFPs) may influence the methylation state of these IAPs. However, the mechanisms underlying the establishment and maintenance of interindividual variability in DNA methylation still remain unclear. Here we report that sequence content and genomic context influence the likelihood that IAPs become variably methylated. IAPs that differ from consensus IAP sequences have altered KZFP recruitment that can lead to decreased KAP1 recruitment when in proximity of constitutively expressed genes. These variably methylated loci have a high CpG density, similar to CpG islands, and can be bound by ZF-CxxC proteins, providing a potential mechanism to maintain this permissive chromatin environment and protect from DNA methylation. These observations indicate that variably methylated IAPs escape silencing through both attenuation of KZFP binding and recognition by ZF-CxxC proteins to maintain a hypomethylated state.

Data availability

All datasets generated in this study have been submitted to GEO under accession code GSE176176.

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

Article and author information

Author details

  1. Kevin R Costello

    Beckman Research Institute, Duarte, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Amy Leung

    Beckman Research Institute, Duarte, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Candi Trac

    Beckman Research Institute, Duarte, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Michael Lee

    Beckman Research Institute, Duarte, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Mudaser Basam

    Beckman Research Institute, Duarte, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. J Andrew Popsilik

    Van Andel Research Institute, Grand Rapids, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Dustin E Schones

    Beckman Research Institute, Duarte, United States
    For correspondence
    dschones@coh.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7692-8583

Funding

National Institutes of Health (R01DK112041)

  • Dustin E Schones

National Institutes of Health (R01CA220693)

  • Dustin E Schones

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

Ethics

Animal experimentation: All animal protocols were in accordance with German and United Kingdom legislation; Project license numbers 80/2098, 80/2497, and 35-9185.81/G-10/94.

Reviewing Editor

  1. Deborah Bourc'his, Institut Curie, France

Publication history

  1. Received: June 9, 2021
  2. Accepted: October 20, 2021
  3. Accepted Manuscript published: October 20, 2021 (version 1)
  4. Version of Record published: October 29, 2021 (version 2)
  5. Version of Record updated: November 5, 2021 (version 3)

Copyright

© 2021, Costello 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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  1. Kevin R Costello
  2. Amy Leung
  3. Candi Trac
  4. Michael Lee
  5. Mudaser Basam
  6. J Andrew Popsilik
  7. Dustin E Schones
(2021)
Sequence features of retrotransposons allow for epigenetic variability
eLife 10:e71104.
https://doi.org/10.7554/eLife.71104
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