Sleeping Endogenous Retroviruses Awaken Your Development


Pedromics
Did you know that approximately 10% of your genome is made up of viral sequences1? These endogenous viral elements belong to a class of genes called retrotransposons, and are also known as endogenous retroviruses (ERVs)2. Retrotransposons occur when a retrovirus integrates its DNA into a germline cell which develops into a viable organism. When the organism reproduces, the ERV can be inherited by the offspring and persist in the genome of their offspring for millions of years. But, just because the sequences are present in the host genome, that does not mean that they are transcribed and able to produce viruses. In fact, most of the ERVs we have are inactivated through mutations acquired during DNA replication, or even partially deleted during recombination events. While these ERVs do not generate viruses, they can play important roles in mammalian biology.
In the last 15 years, ERVs have been found to play important roles in host functions such as reproduction and development3. ERV genomes are flanked by long terminal repeat (LTR) sequences that act as promoters and enhancers, even on genes up to 100 kb away4. For example, the expression of the gene that encodes amylase in humans is promoted by the LTR that is associated with an ERV5. Similarly, the primary promoter for an enzyme important in bile metabolism originates from an LTR6. Most often, LTRs will function as alternate promoters in a tissue-specific manner. Reproductive tissues contain a large fraction of transcriptional variants that have LTRs as promoters. One such example is the gene that codes for aromatase P450, which is an enzyme that is required for estrogen synthesis and is normally expressed in reproductive organs of most mammals7.
A recent set of studies from the CNRS/Université Paris-Sud showed that certain ERVs are essential for the formation of the placenta in mammals8, and are also responsible for the increased muscle mass found in males as compared to females9. The proteins that result from the expression of these ERVs are called syncytins, and they are expressed in all mammals where they contribute to formation of the placenta. This research was done using syncytin knock-out mice. Syncytins also mediate the cell-cell fusion that leads to formation of the syncytiotrophoblast at the fetomaternal interface, which enables the implantation of the placenta in the uterus and is the place where gas and nutrient exchange occurs.
Using the same syncytin knock-out mice, the researchers showed that syncytins are also responsible for the higher muscle mass in males than is found in females. Muscle mass forms from fused stem cells, similar to the syncytiotrophoblast. The syncytin knock-out male mice had 20% fewer muscle fibers than their wild-type male siblings, a number more similar to their wild-type female siblings. Interestingly, female syncytin knock-out mice did not have the same deficit.
It should be noted that this difference in muscle mass was only observed in mice, and still needs to be confirmed in other mammals. Preliminary studies on muscle stem cells from other mammals showed that syncytins contribute to the formation of muscle fibers in all of the species tested (mice, sheep, dogs, and humans). It is unclear whether this is gender-specific from the in vitro studies, however. This muscle mass discrepancy between males and females is not seen in egg-laying animals, so it would be interesting to see if those animals have the same ERVs as mammals. Did ERVs contribute to the emergence of the placental lineage of animals? What other delineating features are ERVs responsible for? Let us know your ideas at tech@biolegend.com!

Warner Bros.
References:
  1. Human endogenous retroviruses: transposable elements with potential?
  2. Endogenous Retroviruses in the Genomics Era.
  3. Endogenous retroviruses in trophoblast differentiation and placental development.
  4. Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance.
  5. Endogenous retroviral sequences are required for tissue-specific expression of a human salivary amylase gene.
  6. Endogenous retroviral LTRs as promoters for human genes: a critical assessment.
  7. Transposable elements in mammals promote regulatory variation and diversification of genes with specialized functions.
  8. Paleovirology of 'syncytins', retroviral env genes exapted for a role in placentation.
  9. Genetic Evidence That Captured Retroviral Envelope syncytins Contribute to Myoblast Fusion and Muscle Sexual Dimorphism in Mice
Contributed by Rea Dabelic, PhD.
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