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 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.
The Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892, USA; Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark;
Gernot
G
Wolf
The Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892, USA;
Peng
P
Yang
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark;
Annette C
AC
Füchtbauer
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark;
Ernst-Martin
EM
Füchtbauer
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark;
Andreia M
AM
Silva
The Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892, USA;
Chungoo
C
Park
The Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892, USA;
Warren
W
Wu
Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
Anders L
AL
Nielsen
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark;
Finn S
FS
Pedersen
The Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892, USA; todd.macfarlan@nih.gov.
Todd S
TS
Macfarlan
D000818:Animals; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D020077:Endogenous Retroviruses / Q000235:genetics* / Q000502:physiology; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D016678:Genome; D006657:Histones / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D014775:Virus Activation / Q000235:genetics; D016662:Virus Integration / Q000235:genetics
D004268:DNA-Binding Proteins; D006657:Histones; C541321:ZFP809 protein, mouse
KRAB zinc finger proteins; endogenous retrovirus; epigenetic silencing; retrovirus restriction factors