If thinking about the billions of bacteria taking up residence in and on your body gives you the willies, you probably won’t find it comforting that humans are also full of viruses. These maligned microbes are actually intertwined in the very fibers of our being—about 8 percent of our genetic material is made up of absorbed forms of retroviruses, the viral family to which HIV, the pathogen that causes AIDS, belongs.
Our intimate relationship with these so-called endogenous retroviruses may be distressing to think about but a study published last week in Cell Reports suggests that they may help shape that thinking by participating in brain development. By manipulating mice genetics, researchers found evidence that some endogenous retroviruses gained new roles that are important for brain development in our not-so-distant rodent relatives. “Brain cells are very complex compared to other cells,” says Johan Jakobsson, a researcher at Lund University in Sweden and lead author of the study. “Co-opting endogenous retroviruses allows for much more complexity, especially since they make up so much of the genome.”
Unlike other viruses, retroviruses contain only RNA and must insert all of their genetic material into their host’s DNA in order to reproduce. When this molecular hijacking happens in sperm or egg cells, the retroviruses can be passed down to the host’s offspring, who then pass them on to their offspring, and so on. Eventually, a combination of mutations and genetic policing detain the viral invader, preventing it from jumping to a new host or even making copies of itself. Many of the endogenous retroviruses in our genome have been imprisoned there for millions of years.
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Most endogenous retroviruses serve a life sentence, and are essentially permanently locked down via a gene-silencing process called DNA methylation. The study by Jakobsson and colleagues suggests that certain endogenous retroviruses don’t serve such a harsh sentence and can get out on parole, so to speak, to carry out important developmental duties in the brains of mouse embryos.
The parole officer in this situation is a protein called TRIM28, which has the ability to put the endogenous retroviruses back on lockdown by a more reversible gene-silencing process, called histone modification. After researchers knocked out TRIM28 in a variety of cells, including liver, brain and white blood cells, they noticed changes in mouse gene expression only in brain cells. “There seems to be a different mechanism regulating endogenous retroviruses in brain cells than in other cells,” Jakobsson says.
Furthermore, reducing the abundance of TRIM28 by deleting only one of the two copies of the gene that encodes it resulted in hyperactive mice. This isn’t enough to conclude that endogenous retroviruses are responsible for these behavioral changes, but taken together with the other findings of this study, they are likely suspects. “This paper provides evidence that endogenous retroviruses play an active role in gene expression in the brain through a dynamic mechanism,” says Guia Guffanti, assistant professor of clinical neurobiology at Columbia University, who was not involved in the study. In this way endogenous retroviruses may help brain cells more intricately regulate their gene expression, thereby allowing them to become more complex.
Determining exactly what these endogenous retroviruses are doing during their periods of limited freedom will require more research, but these experiments suggest that they are somehow involved in brain development—and that is already more than they were once thought to be capable of. Endogenous retroviruses are part of a larger class of genetic material, called transposable elements, that were and often still are dismissed as genetic junk that does little more than take up space in the genome. Studies like this one are slowly changing this assessment. “This brings a completely new perspective on what transposable elements can generate,” Guffanti says.
