The genomic residue of viral infections that occurred long, long ago—even millions of year ago—was once thought to be useless, just part of our so-called junk DNA. Yet these tamped down traces of retroviruses, or endogenous retroviruses (ERVs), may be more active than we realized, even though they are no longer capable of self-replication. These old viruses appear to participate in genetic regulation—specifically within brain cells.

This finding emerged from a study of transcriptional regulation in neural progenitor cells (NPCs). The study, conducted by molecular neurogeneticists at Lund University, suggests that NPCs use a particular molecular mechanism to control the activation of retroviruses. This mechanism involves a corepressor called TRIM28.

The Lund University team, led by Johan Jakobsson, Ph.D., detailed its work January 6 in the journal Cell Reports, in an article entitled, “TRIM28 Represses Transcription of Endogenous Retroviruses in Neural Progenitor Cells.”

“Deletion of TRIM28 in [NPCs] results in high-level expression of two groups of [ERVs]: IAP1 and MMERVK10C,” wrote the authors. “We find that NPCs use TRIM28-mediated histone modifications to dynamically regulate transcription and silencing of ERVs, which is in contrast to other somatic cell types using DNA methylation.”

Somehow, over the course of evolution, the ERVs became integrated with the transcriptional machinery of brain cells. ERVs may play this role in the cells of the brain, and not in the cells of other tissues, because tumors cannot form in nerve cells.

“We have been able to observe that these viruses are activated specifically in the brain cells and have an important regulatory role,” said Dr. Jakobsson. “We believe that the role of retroviruses can contribute to explaining why brain cells in particular are so dynamic and multifaceted in their function. It may also be the case that the viruses' more or less complex functions in various species can help us to understand why we are so different.”

Dr. Jakobsson’s team also found that derepression of ERVs influences transcriptional dynamics in NPCs through the activation of nearby genes and the expression of long noncoding RNAs. In addition, the researchers noted that ERVs are marked by H3K9me3, which is lost upon TRIM28 deletion.

In general, ERVs appear to be an important part of transcriptional regulation in brain cells, helping determine which genes are expressed, and when. Besides offering insights into the most basic workings of brain cells, ERVs may suggest new research paths concerning brain diseases linked to genetic factors.

“Currently, when we look for genetic factors linked to various diseases, we usually look for the genes we are familiar with, which make up a mere 2% of the genome. Now we are opening up the possibility of looking at a much larger part of the genetic material which was previously considered unimportant,” explained Dr. Jakobsson. “The image of the brain becomes more complex, but the area in which to search for errors linked to diseases with a genetic component, such as neurodegenerative diseases, psychiatric illness and brain tumors, also increases.”

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