title: KAP1 controls endogenous retroviruses in embryonic stem cells.
abstract: More than forty per cent of the mammalian genome is derived from retroelements, of which about one-quarter are endogenous retroviruses (ERVs). Some are still active, notably in mice the highly polymorphic early transposon (ETn)/MusD and intracisternal A-type particles (IAP). ERVs are transcriptionally silenced during early embryogenesis by histone and DNA methylation (and reviewed in ref. 7), although the initiators of this process, which is essential to protect genome integrity, remain largely unknown. KAP1 (KRAB-associated protein 1, also known as tripartite motif-containing protein 28, TRIM28) represses genes by recruiting the histone methyltransferase SETDB1, heterochromatin protein 1 (HP1) and the NuRD histone deacetylase complex, but few of its physiological targets are known. Two lines of evidence suggest that KAP1-mediated repression could contribute to the control of ERVs: first, KAP1 can trigger permanent gene silencing during early embryogenesis, and second, a KAP1 complex silences the retrovirus murine leukaemia virus in embryonic cells. Consistent with this hypothesis, here we show that KAP1 deletion leads to a marked upregulation of a range of ERVs, in particular IAP elements, in mouse embryonic stem (ES) cells and in early embryos. We further demonstrate that KAP1 acts synergistically with DNA methylation to silence IAP elements, and that it is enriched at the 5' untranslated region (5'UTR) of IAP genomes, where KAP1 deletion leads to the loss of histone 3 lysine 9 trimethylation (H3K9me3), a hallmark of KAP1-mediated repression. Correspondingly, IAP 5'UTR sequences can impose in cis KAP1-dependent repression on a heterologous promoter in ES cells. Our results establish that KAP1 controls endogenous retroelements during early embryonic development.
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Rowe
authors.forename: Johan
authors.initials: J
authors.lastname: Jakobsson
authors.forename: Daniel
authors.initials: D
authors.lastname: Mesnard
authors.forename: Jacques
authors.initials: J
authors.lastname: Rougemont
authors.forename: Séverine
authors.initials: S
authors.lastname: Reynard
authors.forename: Tugce
authors.initials: T
authors.lastname: Aktas
authors.forename: Pierre V
authors.initials: PV
authors.lastname: Maillard
authors.forename: Hillary
authors.initials: H
authors.lastname: Layard-Liesching
authors.forename: Sonia
authors.initials: S
authors.lastname: Verp
authors.forename: Julien
authors.initials: J
authors.lastname: Marquis
authors.forename: François
authors.initials: F
authors.lastname: Spitz
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Constam
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000107:Acetylation; D000818:Animals; D019175:DNA Methylation; D004622:Embryo, Mammalian / Q000378:metabolism / Q000821:virology; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000821:virology; D020077:Endogenous Retroviruses / Q000235:genetics*; D005347:Fibroblasts; D020868:Gene Silencing; D007426:Genes, Intracisternal A-Particle / Q000235:genetics*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000502:physiology; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D020121:5' Untranslated Regions; D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; D049452:Green Fluorescent Proteins; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28; D008239:Lysine