A transposable element – also known as a jumping gene – appears to help mice survive viral infections.
Transposable elements are sequences of DNA that can replicate and re-insert themselves into the genome. They have spread throughout the genome since complex life emerged and now make up an estimated two-thirds of human DNA. Australian researchers investigating whether transposable elements could adopt functional roles have discovered one in mice, with potential ramifications for the treatment of virus infections which lead to an overactive immune response.
'It shows very clearly that a transposable element can control the immune system to favour host survival following virus infection and it's probably been selected to remain in the genome for this very reason,' said Dr Cecile King from the University of New South Wales in Sydney, who was senior author of the study published in Nature.
Scientists have long suspected that regulatory regions within transposable elements, which regulate their own expression, could be co-opted to regulate nearby genes.
To investigate their function in a complex system, the researchers removed a transposable element from mice using CRISPR/Cas9 and observed the response to infection from Coxsackievirus B4 (CVB4), a virus that largely affects the pancreas.
They selected an ancient transposable element called Lx9c11, located near one of the most highly expressed genes following infection, Schlafen 1. The Schlafen gene family is present in mice and in humans and plays critical roles in the control of virus infection.
Mice without Lx9c11 had lower levels of virus compared to control mice four days after infection. Yet despite increased virus clearance, mice lacking Lx9c11 had poorer chances of survival seven days after infection. It turned out that mice without Lx9c11 had an overactive immune response, similar to that seen in some people with severe COVID-19. Interestingly, replacing the missing Lx9c11 reduced the exaggerated immune response and promoted mouse survival.
The researchers suggest Lx9c11 reduces the immune response by inhibiting Schlafen gene expression. They observed sequence-specific interactions between RNA strands from Lx9c11 and Schlafen 1 which could silence Schlafen.
The authors suggest this illustrates how the immune system is under tight regulation: a strong immune response must be quickly suppressed after clearing the pathogen to avoid the risk of continued tissue damage.
'We think that this is going to be a commonly observed phenomenon, that we're going to learn how transposable elements similar to Lx9c11, control the expression of gene families throughout the genome,' said Dr King.