title: De novo DNA methylation of endogenous retroviruses is shaped by KRAB-ZFPs/KAP1 and ESET.
abstract: Endogenous retroviruses (ERVs) undergo de novo DNA methylation during the first few days of mammalian embryogenesis, although the factors that control the targeting of this process are largely unknown. We asked whether KAP1 (KRAB-associated protein 1) is involved in this mechanism because of its previously defined role in maintaining the silencing of ERVs through the histone methyltransferase ESET and histone H3 lysine 9 trimethylation. Here, we demonstrate that introduced ERV sequences are sufficient to direct rapid de novo methylation of a flanked promoter in embryonic stem (ES) cells. This mechanism requires the presence of an ERV sequence-recognizing KRAB zinc-finger protein (ZFP) and both KAP1 and ESET. Furthermore, this process can also take place on a strong cellular promoter and leads to methylation signatures that are subsequently maintained in vivo throughout embryogenesis. Finally, we show that methylation of ERVs residing in the genome is affected by knockout of KAP1 in early embryos. KRAB-ZFPs, KAP1 and ESET are thus likely to be responsible for the early embryonic instatement of stable epigenetic marks at ERV-containing loci.
authors.affiliation: School of Life Sciences and Frontiers in Genetics Program, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Rowe
authors.forename: Marc
authors.initials: M
authors.lastname: Friedli
authors.forename: Sandra
authors.initials: S
authors.lastname: Offner
authors.forename: Sonia
authors.initials: S
authors.lastname: Verp
authors.forename: Daniel
authors.initials: D
authors.lastname: Mesnard
authors.forename: Julien
authors.initials: J
authors.lastname: Marquis
authors.forename: Tugce
authors.initials: T
authors.lastname: Aktas
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019175:DNA Methylation; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism / Q000821:virology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D020077:Endogenous Retroviruses / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D014162:Transfection; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D004279:DNA, Viral; D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C516239:SETDB1 protein, mouse; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28