As scientists have added to a growing list of types of RNA molecules with roles that go beyond conveying the genetic code, they have found the short strands known as Piwi-interacting RNAs (piRNAs) particularly perplexing. New work from Howard Hughes Medical Institute (HHMI) scientists suggests those abundant molecules may be part of the cell’s search engine, capable of querying the entire history of a cell’s genetic past.
Organisms contain thousands of piRNA molecules, strands of 26 to 31 nucleotides encoded all over the genome. Two recent studies suggest that piRNAs may be responsible for detecting foreign RNA—such as that carried by viruses—relying on a complex search mechanism to reveal whether an invader is foreign based on prior gene activity. piRNAs are found in all animals and some of their functions in some organisms have been explained—but overall they’ve been a very mysterious category of molecule.
In the worm Caenorhabditis elegans, the scientists unexpectedly found that foreign genes that they inserted into the genome were sometimes silenced and sometimes not. When they genetically modified the worm to lack the Piwi protein, the silencing no longer worked. When the researchers probed which sequences piRNAs tended to shut down, they found that if a cell has ever turned on a gene in the past, the piRNA system will recognize it as a “self” gene and allow it to be expressed. But if it hasn’t been active in the organism before, the piRNA will set the silencing mechanism into action so it remains off.
The silencing or lack of silencing is permanent, they found. If the piRNA doesn’t silence a gene the first time it encounters it, it won’t ever silence it. And if it silences it once, then every time that gene appears in the future, the system will turn it off. This is really remarkable, since it implies that an organism has a memory of all the previous gene sequences it’s ever expressed before.
It is believed that the snippets of piRNA do not hold the memory in their sequences. Rather, two other small RNA pathways are thought to provide epigenetic memories of “self” and “non-self” RNA. Mello says piRNAs likely allow mismatched pairing as they scan, so that virtually they can potentially recognize all sequences that have been expressed. Silencing occurs only when a sequence has not been seen before.