How retroviral gene fragments affect embryonic cells

In the nucleus of mouse stem cells, derepressed endoviral RNA molecules (purple) appear in the same spots as RNA polymerase II-containing condensates (green), as shown in this fluorescence microscope image. Credit: Asimi et al.

Ancient and dormant sequences in the genome affect embryonic development in unexpected ways. The mammalian genome contains retroviral sequences that are in an undead but mostly “harmless” state. An international research team recently discovered how some of these retroviral gene fragments affect embryonic cells if they are released. Unexpectedly, not the viral proteins but rather the copies of the genetic material itself throw an imbalance in the cell.

Over thousands of years of evolution, countless viruses have incorporated themselves into our genome. A staggering ten percent of mammalian genomes are ancient retroviral sequences. These no longer seem to pose any danger, because most of them have mutated beyond recognition. Furthermore, these genes have been epigenetically silenced by the cell. But if silencing the viral remains fails, they will rise from their graves again, wreaking havoc in the cell.

“We found that the messenger copies of some of the viral genes, RNA, have a major impact on embryonic cells,” says Denes Hnisz, research group leader at the Max Planck Institute for Molecular Genetics (MPIMG) in Berlin. “The viral sequences appear to recall their original mission of hijacking the molecular machinery that ensures the flow of information from DNA to RNA to proteins. Interestingly, messenger RNA itself appears to be responsible.”

Hnisz’s team and collaborating researchers have published their findings in the journal Genetics of nature. They describe that the RNA from resurrected viruses exerts attractive forces on enzymes that read information from DNA. The tasks of the embryonic cell, such as reading important embryonic genes, are neglected and a fatal imbalance develops. This triggered state occurs, for example, in some cancers and neurological diseases.

Viruses are cleverly constructed bits of genetic information. Some of them incorporate themselves into the genome of their hosts and persist there. Thousands of copies of endogenous retroviruses (ERVs) have spread throughout mammalian genomes, often in repetitive droves of hundreds of copies.

“When retroviruses jump from one section of DNA to another during their life cycle, they can alter genes and even recombine them. This makes them an important tool for evolution to create new genes,” says Henri Niskanen, one of the scientists involved in the study. “For an individual organism, however, uncontrolled gene editing does not bode well, especially during embryonic development.”

This is why the cell will identify ERV sequences and recruit dedicated repressive machinery at their sites and keep them silent. Also, the chromosome gets compacted at these sites.

But what happens if you disable these protection mechanisms? The research team wanted to find out what is the very first thing that happens when ERV zombies are no longer under control. To do this, they removed Trim28, a protein responsible for silencing viral remnants, from mouse embryonic stem cells, and monitored its immediate consequences.

Once Trim28 disappeared, the cell unsurprisingly read more ERV genes, making copies of RNA with the help of the enzyme RNA polymerase. But unexpectedly, the polymerase simultaneously disappeared from stem cell genes that are especially important for stem cell potency.

“Only a limited pool of polymerase enzymes and other required factors is available in each cell,” says Christina Riemenschneider, another researcher on the team. If too many genes are transcribed at once, they will compete for limited resources, she says. In one experiment, repeats of ERV sequences competed against stem cell genes. “We see that the ERV repeats have a slightly higher affinity. They take the mechanism away from the embryonic genes, creating an imbalance,” says Riemenschneider.

RNA polymerase and other necessary factors that selectively dock with genes often assemble into droplets that contain lots of protein and float around in the cell nucleus, much like oil droplets in a salad dressing. These “condensates” contain many of the molecules needed to read genes and are particularly attracted to specific segments of DNA that control a cell’s most important genes.

The ERV genes, or rather the RNA molecules made using these genes, seemed to literally hijack the condensates. In high-resolution microscopic images, they were often found in the same locations as the reactivated ERV genes. After the viral RNA was removed from the cells, the droplets returned to their original positions.

The effects of virus-like RNA weren’t limited to the molecular level. Working on early mouse embryos, the research team demonstrated that shifting condensates to ERVs had negative effects on development. Stem cells, for example, lost the characteristic property of being able to develop into any other cell because the necessary genes were no longer active.

“It’s quite extraordinary that non-coding, non-functional genes have such a profound effect via RNA,” says scientist Abhishek Sampath Kumar, who was involved in the work. “You might imagine DNA damage or virus particles when you think of retroviruses integrating into the genome, but that’s not the case here.”

As a result, the team of scientists say their discovery puts research on endogenous retroviruses in a new light. “The hijacking of transcriptional condensates by ERVs and their RNA is an important mechanistic finding that should be considered in future studies of transposable elements and their epigenetic regulators,” says lead researcher Vahid Asimi, who worked on the study . “This could be an additional pathway used by ERVs to contribute to evolutionary innovation.”

“ERV reactivation is clearly linked to pathologies, from obesity to various cancers to neurological diseases such as amyotrophic lateral sclerosis and schizophrenia,” adds group leader Denes Hnisz. “Hopefully, our research will help elucidate the molecular causes of these diseases.”

More information:
Vahid Asimi et al, Hijacking of transcriptional condensates by endogenous retroviruses, Genetics of nature (2022). DOI: 10.1038/s41588-022-01132-w

Provided by the Max Planck Institute for Molecular Genetics

Citation: Zombie Viruses During a Hijacking Journey: How Retroviral Gene Fragments Affect Embryonic Cells (2022, Nov. 23) Retrieved Nov. 23, 2022 from hijacking-retroviral-gene. html

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