KRAB-zinc finger protein gene expansion in response to active retrotransposons in the murine lineage
- The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, United States
- Ecole Polytechnique Fédérale de Lausanne, Switzerland
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).
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Evollutionally dynamic L1 regulation in embryonic stem cellsNCBI Gene Expression Omnibus, GSM1406445.
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H3K9me3_ChIPSeq (Ctrl)NCBI Gene Expression Omnibus, GSM1327148.
Article and author information
Author details
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.
Reviewing Editor
- Deborah Bourc'his, Institut Curie, France
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.
Version history
- Received: February 24, 2020
- Accepted: May 31, 2020
- Accepted Manuscript published: June 1, 2020 (version 1)
- 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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KRAB-zinc finger protein gene expansion in response to active retrotransposons in the murine lineage
eLife 9:e56337.
https://doi.org/10.7554/eLife.56337
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