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

Elife. 2020 Jun 1;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.

Keywords: KRAB-ZFP; chromatin; chromosomes; development; evolution; gene expression; genetics; genomics; mouse; retrotransposons; transposable elements.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

Associated data

  • GEO/GSE115291
  • GEO/GSM1406445
  • GEO/GSM1327148