All living organisms are in a constant arms race against viruses and other genetic parasites that want us to propagate their genes. Just as bacteria have developed CRISPR-Cas as a counter weapon, animals and humans have developed similar defence mechanisms. In the latest issue of Nature, a young Danish scientist reveals that cells hack into their own genome to stop attacks from genetic parasites.
To ensure their survival, genetic parasites such as viruses and transposable elements - socalled transposons - continually need to make new copies of themselves. They therefore try to lure their host into copying and propagating their genes. Human genomes are under constant attack by these parasites, which insert their DNA into our genomes. To tame these selfish mobile genes, cells need to be able to prevent copying by genetic parasites. At the same time, however, the cells must make small RNA copies of the invasive genes, since the cells use these molecules to determine where the genetic parasites are located. Researchers have now solved the mystery of how cells do this.
“We have long known that cells pack locations in the genome in a way that prevents them from being copied. There has therefore been a longstanding paradox about how the cells can still make small RNA copies of exactly these genetic locations. Our new study shows that the cells do this by hacking into their own RNA copying system, known as transcription machinery, enabling them to make small copies to help them battle the invasive genetic parasites,” explains Peter Refsing Andersen, a Danish postdoctoral fellow at the Institute of Molecular Biology in Vienna, Austria and lead author of the article in the prestigious journal Nature.
A molecular mystery
In this study, the researchers worked with fruit flies (Drosophila melanogaster), which share many genes and genetic mechanisms with humans. The researchers discovered how fruit flies manage to make small copies of these tightly packed DNA sequences so that they can build up genetic memory. This corresponds to immune defence at the DNA level that enables them to fight back against the genetic parasites.
“This is no trivial task, because fruit flies have really hidden these genome sequences far away to avoid helping the parasites by copying their DNA. Nevertheless, the fruit flies need to know these sequences to be able to recognize and prevent entry by other genetic parasite sequences. This is therefore really a molecular mystery.”
In many ways, this system is like the renowned bacterial defence system CRISPR-Cas discovered a few years ago. It is now considered to be a transformative tool in gene technology because the bacteria programme the CRISPR-Cas system to enable them to attack the DNA sequences of a specific virus with the help of a tiny RNA copy of the virus’s DNA sequences the bacteria had acquired previously.
“Similar to CRISPR-Cas, the fruit flies have to make small RNA copies so they can remember and recognize various genetic parasites. However, the cells have packed the parasite sequences very compactly in the form of heterochromatin, which the cells’ usual transcription machinery cannot read. They therefore have to hack into their own system to be able to make the necessary RNA copies.”
Time to make a mistake
Fruit flies hack into their own genome by assembling an arsenal of tools that enable them to transcribe heterochromatin sequences. Specifically, the cells have built a pathway that can transcribe heterochromatin without forcing it to convert to the active type of DNA, known as euchromatin.
“This is similar to IKEA hacking: modifying and reconnecting pieces of furniture so that new functions and uses emerge. Similarly, cells have connected copies of genes that normally function in both gene activation and gene silencing. These genes encode at least five proteins that can work together to activate the transcription of the heterochromatin and then immediately silence this. The cells can thereby make the small RNA copies without helping the genetic parasites unnecessarily.”
Peter Refsing Andersen originally hypothesized that this mechanism worked completely differently. Based on the literature and his PhD studies, he hypothesized that fruit flies, while transcribing genes neighbouring genetic parasites, could ignore the stop signals and continue transcribing the heterochromatin. However, this hypothesis turned out to be incorrect.
“This is a good example of how your initial hypothesis is seldom correct when you thoroughly research a field. I have basically resolved the paradox I wrote about in my application for my postdoctoral fellowship, but the result was the opposite of what I had thought. We spent almost a year attempting to prove our hypothesis before I had to follow the results and change the model on which my research was based. If I had only been awarded a 2-year fellowship, I would not have had the time to do this, and then we would probably not have been able to publish an article in Nature today.”
The struggle within the gonads
Similar to CRISPR-Cas, research on the transcription of heterochromatin may prove to be the start of something big. Today, researchers know that less than 2% of our genome is actual coding gene sequences: the locations in which our cells encode the proteins that comprise the building blocks of the body’s structure and function. By contrast, two thirds of our genome consist of genetic parasites and their fragments from previous invasions over millions of years.
“We call these sequence elements genetic parasites because they do not seem to have a real function in the body – other than likely creating new diversity in our genes. They do this because they can move around in the genome. This can result in benefits but can also lead to deadly mutations and sterility. And we still do not fully understand how cells keep these transposable genetic parasites in check.”
The researchers hope that understanding cells better will enable them to understand what happens when the genetic defence systems malfunction. So far, the researchers have only discovered this transcription system in the fruit fly and, more precisely, only in the female gonads (the ovaries). However, there is a really good explanation for this.
“The genetic parasites have chosen the battleground. Genetic parasites do not really benefit from making copies of themselves in normal cells. Massively propagating their DNA requires attacking the gonads, because only these cells provide an opportunity to spread new genetic parasite copies to the next generations. It is therefore not surprising that this defence system only exists there.”
In fruit flies, errors in the hacked transcription system often result in sterile females. It is still not known whether humans, which are similar genetically to fruit flies, have the same genetic defence system and whether its flaws have similar effects. Nevertheless, the researchers have discovered that mice and humans have one of the key genes fruit flies use in their hacking mechanism.
“We do not yet know whether this system is identical in humans, but we undoubtedly have a corresponding system. As we begin to sequence the genomes of more and more people, we will learn much more about how the human system functions, including the effects of flaws in this defence system and how we can correct them,” concludes Peter Refsing Andersen.
“A heterochromatin-dependent transcription machinery drives piRNA expression” has been published in Nature. In 2014, the Novo Nordisk Foundation awarded a postdoctoral fellowship for study abroad in Vienna, Austria to lead author Peter Refsing Andersen for the project "Breaking Down the Rules of Transcription in Defence of the Genome".