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

• DOI: 10.7554/elife.56337
• Publication Date: 2020-06-01T12:00:18Z
• Authors: Gernot Wolf; Alberto de Iaco; Ming-An Sun; Melania Bruno; Matthew Tinkham; Don Hoang; Apratim Mitra; Sherry Ralls; Didier Trono; Todd S Macfarlan
• Keywords: 0301 basic medicine; chromosomes; Retroelements; QH301-705.5; Science; Evolution, Molecular; Mice; 03 medical and health sciences; evolution; genomics; Animals; genetics; Biology (General); development; mouse; Gene Editing; Mice, Knockout; KRAB-ZFP; Q; R; Zinc Fingers; DNA; Chromosomes and Gene Expression; retrotransposons; Repressor Proteins; Mutation; gene expression; DNA Transposable Elements; chromatin; Medicine; transposable elements; CRISPR-Cas Systems

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.