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Jul. 1, 2016 Research Highlight Biology

Keeping viral DNA at bay

Scientists find that an epigenetic interplay keeps virus-derived DNA sequences repressed in embryos but not in the surrounding placenta

Image of mouse embryo Figure 1: Wild-type (left), Dnmt1-lacking (center) and Np95-lacking (right) mouse embryos. Only the Dnmt1 mutant shows activity of endogenous retroviruses, shown in blue. Reprinted from Ref. 1, Copyright 2016, with permission from Elsevier.

The human genome is riddled with virus-derived sequences considered to be remnants of viral infections during our evolutionary past. A new study by RIKEN researchers explains how these so-called endogenous retroviruses (ERVs) are repressed in the developing embryo, but also finds that they spring into action in the cells of the placenta1.

“In my field, people mostly think that ERVs are harmful and therefore should be silenced in all cells,” says Jafar Sharif of the RIKEN Center for Integrative Medical Sciences, who led the study with colleagues at RIKEN and collaborators in Japan, Canada and the US. “But our work shows that ERV expression takes place even under perfectly normal conditions, such as in the placenta during development.”

Sharif and his colleagues first wanted to clarify how these viral sequences are silenced in the embryonic lineage.

An enzyme called DNMT1 was known to help to inactivate these rogue genetic elements by ensuring that methyl tags are placed in the right locations on the DNA backbone to maintain proper gene expression and regulation.

When functioning DNMT1 is absent, the viral elements kick into action, which was thought to be due to a lack of DNA methylation. But that turned out to be only part of the story. The RIKEN team has shown that the partially methylated DNA wrought by depletion of DNMT1 actually attaches itself to a second protein called NP95, which triggers the regulatory cascade responsible for releasing the brakes on viral repression.

Image of Jafar Sharif Figure 2: Jafar Sharif is studying endogenous retroviruses in developing embryos. © 2016 RIKEN

The researchers discovered that prolonged binding with NP95 disrupted the way DNA was packaged into chromatin fibers and allowed ERVs to be expressed. They confirmed the crucial role of Np95 by removing the protein in mouse embryos, either alone or in combination with Dnmt1 removal. In both cases, the viruses remained dormant (Fig. 1).

“I was very surprised,” says Sharif of this unexpected finding. “In fact, at first I thought my experiments were not going well when I found deleting the Np95 gene together with the Dnmt1 gene inexplicably extinguished the activation of ERVs.”

But more surprising was that the Np95 protein and ERVs are highly expressed in placental cells.

This discrepancy between ERV activity in embryonic and extra-embryonic tissues remains a mystery. “There is still no physiological explanation for why these ERVs are expressed in the placenta,” notes Sharif, who intends to find out why. “I like to think that ERV expression must have some biological meaning, or else it would not be tolerated in the placenta,” Sharif says.

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References

  • 1. Sharif, J., Endo, T. A., Nakayama, M., Karimi, M. M., Shimada, M., Katsuyama, K., Goyal, P., Brind’Amour, J., Sun, M.-A., Sun, Z. et al. Activation of endogenous retroviruses in Dnmt1−/− ESCs involves disruption of SETDB1-mediated repression by NP95 binding to hemimethylated DNA. Cell Stem Cell advance online publication, 14 April 2016. doi: 10.1016/j.stem.2016.03.013

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