eLife (Jun 2020)

KRAB-zinc finger protein gene expansion in response to active retrotransposons in the murine lineage

  • Gernot Wolf,
  • Alberto de Iaco,
  • Ming-An Sun,
  • Melania Bruno,
  • Matthew Tinkham,
  • Don Hoang,
  • Apratim Mitra,
  • Sherry Ralls,
  • Didier Trono,
  • Todd S Macfarlan

DOI
https://doi.org/10.7554/eLife.56337
Journal volume & issue
Vol. 9

Abstract

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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.

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