Lausanne, Switzerland. Viral "squatters" comprise nearly half of our genetic code. Millions of years ago, genomic invaders inserted their DNA into our own when they infected our ancestors. But how we keep them quiet and prevent them from attack was a mystery.

Much of the mammalian genome is derived from dispersed and repeated DNA elements capable of inserting replicas of themselves into novel genomic locations. Most organisms have them and a significant proportion are endogenous retroviruses (ERVs) that derive from ancient viral infections of germ cells in humans, mammals and other vertebrates, passed on down the generations in an organism's tissues or cells (endogenous).

The reason we survive the presence of these endogenous retroviruses — viruses that attack and are passed on through germ cells, the cells that give rise to eggs and sperm — is because something keeps the killers silent. ERVs are transcriptionally silenced during early embryogenesis by histone and DNA methylation, but the initiators of this process are largely unknown.

This research shows KAP1 deletion leads to a marked upregulation of a range of ERVs in mouse embryonic stem cells and in early embryos. Didier Trono and Helen Rowe from the Ecole Polytechnique Fédérale de Lausanne (EPFL) published the team findings in the journal Nature.

The actions of related genes can be coordinated by a master regulatory protein that recognizes a group of similar but not identical DNA sequences, while ignoring more distantly related sequences. The work yields insights into evolution and gene expression/silencing, as well as potential new therapies for treating other retrovirus-based maladies (e.g., HIV).

By analysing embryonic stem cells in mice within the first few days of life, Trono and his team discovered that mouse DNA codes for an army of auxiliary proteins that recognize the numerous viral sequences littering the genome.

The researchers also demonstrated that a master regulatory protein called KAP1 appears to orchestrate these inhibitory proteins in silencing would-be viruses. When KAP1 is removed, for example, the viral DNA "wakes up," multiplies, induces innumerable mutations, and the embryo soon dies.

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Interview: Didier Trono and The Viruses Within. Endogenous retroviruses are part of our DNA. Researchers from the Ecole Polytechnique Fédérale de Lausanne (EPFL) in Switzerland have discovered the mechanism that protects us from these hosts. This research may help developing new therapeutics for serious infections.

Video courtesy of Video courtesy of the EPFL.. Time: 00:03:22.

Because retroviruses tend to mutate their host's DNA, they have an immense power and potential to alter genes.

Some individuals silenced the retrovirus during ancient pandemics, then passed on their ability. Great waves of endogenous retrovirus coincide with the times evolution seemed to leap ahead.

"In our genome we find traces of the last two major waves. The first took place 100 million years ago, at the time when mammals started to develop, and the second about fifty million years ago, just before the first anthropoid primates," he says.

Discovery of the KAP1 mechanism could stimulate the search for new therapeutic approaches for AIDS.

The virus that causes AIDS can lie dormant in the red blood cells it infects, keeping it hidden from potential treatments. Waking the virus up could expose it to attack.

ParticipantsDidier Trono's co-authors include Helen M. Rowe, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Switzerland; Johan Jakobsson, EPFL and Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, Sweden; Daniel Mesnard, EPFL; Jacques Rougemont, EPFL; Séverine Reynard, EPFL; Tugce Aktas, EMBL Heidelberg, Germany; Pierre V. Maillard, EPFL; Hillary Layard-Liesching, EPFL; Sonia Verp, EPFL; Julien Marquis, EPFL; François Spitz, EMBL Heidelberg, Germany; Daniel B. Constam, EPFL; and Didier Trono, EPFL.

CitationKAP1 controls endogenous retroviruses in embryonic stem cells. Helen M. Rowe, Johan Jakobsson, Daniel Mesnard, Jacques Rougemont, Séverine Reynard, Tugce Aktas, Pierre V. Maillard, Hillary Layard-Liesching, Sonia Verp, Julien Marquis, François Spitz, Daniel B. Constam and Didier Trono. Nature 2009; 463: 237-240. doi:10.1038/nature08674

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.

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