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 PMID:25737282  

The KRAB zinc finger protein ZFP809 is required to initiate epigenetic silencing of endogenous retroviruses.

Gernot Wolf | Peng Yang | Annette C Füchtbauer | Ernst-Martin Füchtbauer | Andreia M Silva | Chungoo Park | Warren Wu | Anders L Nielsen | Finn S Pedersen | Todd S Macfarlan
Genes & development | 2015

Retroviruses have been invading mammalian germlines for millions of years, accumulating in the form of endogenous retroviruses (ERVs) that account for nearly one-tenth of the mouse and human genomes. ERVs are epigenetically silenced during development, yet the cellular factors recognizing ERVs in a sequence-specific manner remain elusive. Here we demonstrate that ZFP809, a member of the Krüppel-associated box zinc finger protein (KRAB-ZFP) family, initiates the silencing of ERVs in a sequence-specific manner via recruitment of heterochromatin-inducing complexes. ZFP809 knockout mice display highly elevated levels of ZFP809-targeted ERVs in somatic tissues. ERV reactivation is accompanied by an epigenetic shift from repressive to active histone modifications but only slight destabilization of DNA methylation. Importantly, using conditional alleles and rescue experiments, we demonstrate that ZFP809 is required to initiate ERV silencing during embryonic development but becomes largely dispensable in somatic tissues. Finally, we show that the DNA-binding specificity of ZFP809 is evolutionarily conserved in the Muroidea superfamily of rodents and predates the endogenization of retroviruses presently targeted by ZFP809 in Mus musculus. In sum, these data provide compelling evidence that ZFP809 evolved to recognize foreign DNA and establish histone modification-based epigenetic silencing of ERVs.

Pubmed ID: 25737282

Associated grants

  • Agency: NCRR NIH HHS, United States
    Id: U42 RR024244
  • Agency: NICHD NIH HHS, United States
    Id: HD008933
  • Agency: NHGRI NIH HHS, United States
    Id: U01HG004085
  • Agency: NHGRI NIH HHS, United States
    Id: U01 HG004080
  • Agency: Wellcome Trust, United Kingdom
  • Agency: NHGRI NIH HHS, United States
    Id: U01 HG004085
  • Agency: NCRR NIH HHS, United States
    Id: U42RR024244
  • Agency: NHGRI NIH HHS, United States
    Id: U01HG004080

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