Nature 463, 237-240 (14 January 2010) | doi:10.1038/nature08674; Received 24 September 2009; Accepted 11 November 2009

KAP1 controls endogenous retroviruses in embryonic stem cells

Helen M. Rowe1, Johan Jakobsson1,3, Daniel Mesnard1, Jacques Rougemont1, Séverine Reynard1, Tugce Aktas2, Pierre V. Maillard1, Hillary Layard-Liesching1, Sonia Verp1, Julien Marquis1, François Spitz2, Daniel B. Constam1 & Didier Trono1

  1. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
  2. EMBL Heidelberg, Meyerhofstrasse 1, 69117 Heidelberg, Germany
  3. Present address: Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, 22184 Lund, Sweden.

Correspondence to: Didier Trono1 Correspondence and requests for materials should be addressed to D.T. (Email: didier.trono@epfl.ch).

More than forty per cent of the mammalian genome is derived from retroelements, of which about one-quarter are endogenous retroviruses (ERVs)1. Some are still active, notably in mice the highly polymorphic early transposon (ETn)/MusD and intracisternal A-type particles (IAP)2, 3. ERVs are transcriptionally silenced during early embryogenesis by histone and DNA methylation4, 5, 6 (and reviewed in ref. 7), although the initiators of this process, which is essential to protect genome integrity8, 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 complex9, 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 embryogenesis10, and second, a KAP1 complex silences the retrovirus murine leukaemia virus in embryonic cells11, 12, 13. 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.


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