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

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...

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Bibliographic Details
Published in:Genes & development 2015-03, Vol.29 (5), p.538-554
Main Authors: Wolf, Gernot, Yang, Peng, Füchtbauer, Annette C, Füchtbauer, Ernst-Martin, Silva, Andreia M, Park, Chungoo, Wu, Warren, Nielsen, Anders L, Pedersen, Finn S, Macfarlan, Todd S
Format: Article
Language:English
Subjects:
Animals
Binding Sites
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Embryo, Mammalian
Endogenous Retroviruses - genetics
Endogenous Retroviruses - physiology
Epigenesis, Genetic
Gene Silencing
Genome
Histones - metabolism
Mice
Mice, Knockout
Mus musculus
Protein Binding
Research Paper
Retrovirus
Virus Activation - genetics
Virus Integration - genetics
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.252767.114