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KAP1 controls endogenous retroviruses in embryonic stem cells

Nature volume 463, pages 237–240 (2010)Cite this article

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Abstract

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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Figure 1: IAP elements are upregulated in KAP1-depleted ES cells.
Figure 2: KAP1 controls IAP elements in embryogenesis.
Figure 3: KAP1 is enriched at the 5′UTR of IAP genomes and loss of KAP1 leads to loss of H3K9me3 and an increase in H4 acetylation.
Figure 4: IAP 5′UTR sequences expressed in KAP1-depleted ES cells are polymorphic and can repress a GFP reporter in a KAP1-dependent way.

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Acknowledgements

We thank P. Turelli and I. Barde for advice, F. Cammas and R. Losson for the Kap1loxp/loxP and Kap1+/- mice, D. Schultz for the KAP1-specific antibody, and K. Harshman at the genomics platform for the Illumina high throughput sequencing. This work was supported by grants from the Swiss National Science Foundation, the Infectigen Association and the Strauss Foundation to D.T., and by a post-doctoral fellowship from the Swedish Research Council to J.J.

Author Contributions H.M.R. performed experiments, with contributions from S.R., T.A., P.V.M., H.L.-L., S.V. and J.M. J.J. developed conditional KAP1-knockout ES cell lines, D.M. performed dissection and in situ hybridisation of embryos and J.R. did bioinformatics analyses. P.V.M., F.S., D.B.C., D.M. and J.J. contributed to experimental design. D.T. and H.M.R. designed the study, analysed the results and wrote the manuscript.

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  1. Johan Jakobsson

    Present address: Present address: Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, 22184 Lund, Sweden.,

Authors and Affiliations

  1. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland ,

    Helen M. Rowe, Johan Jakobsson, Daniel Mesnard, Jacques Rougemont, Séverine Reynard, Pierre V. Maillard, Hillary Layard-Liesching, Sonia Verp, Julien Marquis, Daniel B. Constam & Didier Trono

  2. EMBL Heidelberg, Meyerhofstrasse 1, 69117 Heidelberg, Germany ,

    Tugce Aktas & François Spitz

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Rowe, H., Jakobsson, J., Mesnard, D. et al. KAP1 controls endogenous retroviruses in embryonic stem cells. Nature 463, 237–240 (2010). https://doi.org/10.1038/nature08674

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