1. Chromosomes and Gene Expression
  2. Genetics and Genomics
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KRAB-zinc finger protein gene expansion in response to active retrotransposons in the murine lineage

  1. Gernot Wolf
  2. Alberto de Iaco
  3. Ming-An Sun
  4. Melania Bruno
  5. Matthew Tinkham
  6. Don Hoang
  7. Apratim Mitra
  8. Sherry Ralls
  9. Didier Trono
  10. Todd S Macfarlan  Is a corresponding author
  1. The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, United States
  2. Ecole Polytechnique Fédérale de Lausanne, Switzerland
Research Article
  • Cited 9
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Cite this article as: eLife 2020;9:e56337 doi: 10.7554/eLife.56337

Abstract

The Krüppel-associated box zinc finger protein (KRAB-ZFP) family diversified in mammals. The majority of human KRAB-ZFPs bind transposable elements (TEs), however, since most TEs are inactive in humans it is unclear whether KRAB-ZFPs emerged to suppress TEs. We demonstrate that many recently emerged murine KRAB-ZFPs also bind to TEs, including the active ETn, IAP, and L1 families. Using a CRISPR/Cas9-based engineering approach, we genetically deleted five large clusters of KRAB-ZFPs and demonstrate that target TEs are de-repressed, unleashing TE-encoded enhancers. Homozygous knockout mice lacking one of two KRAB-ZFP gene clusters on chromosome 2 and chromosome 4 were nonetheless viable. In pedigrees of chromosome 4 cluster KRAB-ZFP mutants, we identified numerous novel ETn insertions with a modest increase in mutants. Our data strongly support the current model that recent waves of retrotransposon activity drove the expansion of KRAB-ZFP genes in mice and that many KRAB-ZFPs play a redundant role restricting TE activity.

Data availability

All NGS data has been deposited in GEO (GSE115291). Sequences of full-length de novo ETn insertions have been deposited in the GenBank database (MH449667- MH449669).

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

Article and author information

Author details

  1. Gernot Wolf

    The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Alberto de Iaco

    School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Ming-An Sun

    The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Melania Bruno

    The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8401-7744
  5. Matthew Tinkham

    The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Don Hoang

    The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Apratim Mitra

    The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Sherry Ralls

    The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Didier Trono

    School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3383-0401
  10. Todd S Macfarlan

    The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, United States
    For correspondence
    todd.macfarlan@nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2495-9809

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (1ZIAHD008933)

  • Todd S Macfarlan

Swiss National Science Foundation (310030_152879)

  • Didier Trono

Swiss National Science Foundation (310030B_173337)

  • Didier Trono

European Research Council (No. 268721)

  • Didier Trono

European Research Council (No 694658)

  • Didier Trono

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 studies using mice were performed in accordance to the Guide for the Care and Use of Laboratory Animals of the NIH, under IACUC animal protocol (ASP )18-026.

Reviewing Editor

  1. Deborah Bourc'his, Institut Curie, France

Publication history

  1. Received: February 24, 2020
  2. Accepted: May 31, 2020
  3. Accepted Manuscript published: June 1, 2020 (version 1)
  4. Version of Record published: June 11, 2020 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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