Viral proteins may regulate human embryonic development

“Does the virus selfishly benefit by switching itself on in these early embryonic cells?” said Grow. “Or is the embryo instead commandeering the viral proteins to protect itself? Can they both benefit? That’s possible, but we don’t really know.”

“There is a long-standing debate within the field of genome evolution,” Grow said. “Why retain so much seemingly useless and repetitive DNA within our genomes? Our results demonstrate a tangible and physiologically relevant phenotype — improved antiviral immunity. This clearly implicates HERVK expression in the embryo as a potentially beneficial strategy.”

Battle or symbiosis?

Although there’s no direct evidence yet that HERVK reactivation provides a selective advantage for human development, the study’s results are intriguing, said Wysocka.

Information about Stanford’s Department of Chemical and Systems Biology and Department of Developmental Biology, both of which also supported the work, is available at and

“The mere observation that viral proteins are expressed and able to engage cellular machinery in complex ways shows that in order to fully comprehend intricacies of early human development, we need to consider the function of these genome invaders,” she said.

Does the virus selfishly benefit by switching itself on in these early embryonic cells?

Grow and his colleagues found that some HERVK viruses are transcribed into RNA — the first step in making proteins based on the blueprint provided by DNA— in 3- to 4-day-old embryos. This viral activation coincides with the activation of other key human genes in the embryo. The researchers then used electron microscopy to observe what appear to be intact viral particles in human blastocysts, which arise within five to six days after fertilization.

Much remains to be known, but it’s clear the fates of both are intertwined within days of conception. “Our early human development is unique and depends on genes and DNA sequences we picked up recently in our evolutionary history,” said study co-author Renee Reijo Pera, PhD, who is a former professor of obstetrics and gynecology at Stanford. She is now on the faculty of Montana State University. “What we’re learning now is that our ‘junk DNA,’ including some viral genes, is recycled for development in the first few days and weeks of life.”

Most of these sequences are inactive in mature cells, but recent research has shown that they can spring to life in tumor cells or in human embryonic stem cells. A study published in February in Cell Stem Cell by researchers from Singapore’s Genome Institute showed that sequences from a primate virus called HERVH are also activated in early human development.

‘A potentially beneficial strategy’

Researchers found that Rec not only affected the expression of viral genes, but it also binds to many RNAs made from human genes. Rec also modulates the RNAs’ interactions with the ribosomes. Finally, the presence of Rec in human cells stimulated an immune response that increased the amount of a surface-bound human protein called IFITM1, which protects the cells from viral infection.

Now the Stanford researchers have shown for the first time that viral proteins are abundantly present in the developing human embryo and assemble into what appear to be viral particles in electron microscopy images. By following up with additional studies in human embryonic cells grown in vitro, scientists showed that these viral proteins affect gene expression in the developing embryo and may protect the cells from infection by other viruses.

Other Stanford authors are graduate students Ryan Flynn, Nicholas Bayless, Daniel Wesche and Lance Martin; postdoctoral scholars Shawn Chavez, PhD, and Mark Wossidlo, PhD; assistant professor of medicine Catherine Blish, MD, PhD; and professor of dermatology Howard Chang, MD, PhD.

But it’s not clear whether this sequence of events is the result of thousands of years of co-existence, a kind of evolutionary symbiosis, or if it represents an ongoing battle between humans and viruses.

HERVK also encodes a viral protein called Rec, which binds to viral RNA transcripts made from DNA sequences, and escorts the transcripts to the ribosomes in the cells’ cytoplasm to be made into proteins.

The research was supported by the National Institutes of Health (grants DP2AI11219301, HG007735 and HL100397), the National Science Foundation, the Smith Family Foundation, the California Institute for Regenerative Medicine, and the March of Dimes.

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