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

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...

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Bibliographic Details
Published in:eLife 2020-06, Vol.9
Main Authors: Wolf, Gernot, de Iaco, Alberto, Sun, Ming-An, Bruno, Melania, Tinkham, Matthew, Hoang, Don, Mitra, Apratim, Ralls, Sherry, Trono, Didier, Macfarlan, Todd S
Format: Article
Language:English
Subjects:
Amino acids
Animals
Binding sites
chromatin
Chromosome 2
Chromosome 4
Chromosomes and Gene Expression
CRISPR
CRISPR-Cas Systems
Deoxyribonucleic acid
development
DNA
DNA - chemistry
DNA - genetics
DNA - metabolism
DNA binding proteins
DNA Transposable Elements - genetics
Embryos
Enhancers
evolution
Evolution, Molecular
Gene clusters
Gene Editing
Gene expression
Genetics and Genomics
Genomes
House mouse
KRAB-ZFP
Mice
Mice, Knockout
Mutants
Mutation - genetics
Plasmids
Repressor Proteins - chemistry
Repressor Proteins - genetics
Repressor Proteins - metabolism
Retroelements - genetics
retrotransposons
transposable elements
Transposons
Zinc finger proteins
Zinc Fingers - genetics
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/elife.56337