How ancient viral sequences hijack limb development
New research from the Mundlos lab reveals how viral-like particles cause a developmental malformation.
Transposable elements are genetic sequences that can relocate within the genome, potentially causing mutations and disease. Now, the lab of Stefan Mundlos has identified the mechanism by which a retrotransposon from viral origin leads to limb malformations in mice. The team demonstrates that the retrotransposon adopts regulatory sequences, mediating its expression during embryonic limb formation. This leads to the production of viral-like particles in specific cells of the developing limb. Although not infecting other cells, these particles cause the premature death of cells responsible for digit outgrowth. The results show that aberrant activation of retroviral elements can cause congenital malformations. This new disease mechanism might be the cause for developmental disorders that so far remain poorly understood. The findings are now published in Nature Genetics.
Over millennia, viruses have left their mark on the human genome. Nearly half of it consists of transposable elements (TEs) – mobile genetic sequences that have colonized our genome by shifting location. Many TEs are remnants of retroviruses that once integrated into the genomes of our ancestors. TEs are a double-edged sword: while some have physiological functions – during development, for example – their activity is tightly regulated by epigenetic mechanisms and other means. When this regulation fails, TEs can mobilize and disrupt gene expression, leading to disease. In their current study, the researchers discovered a novel mechanism by which TEs cause pathology, without directly altering gene expression.
“My interest in joining Stefan Mundlos’ lab was to understand how transposable elements can influence genome regulation during embryo formation,” says Juliane Glaser, who conducted the research as a postdoc at the MPIMG. The Mundlos lab has long focused on uncovering the role of the non-coding genome in rare genetic diseases. In their current study, the scientists now focused on Dactylaplasia, a mouse limb malformation that resembles human ectrodactyly and is characterized by missing digits on the hand or feet. This malformation was shown to be caused by a transposable element of viral origin inserted near the Fgf8 gene, which is involved in limb formation. “Based on previous research, it was believed that the transposable element insertion would disrupt the protein-coding gene, leading to the observed phenotype,” Juliane Glaser explains.
The team has now demonstrated that this is not the case. Instead, the TE produces a product that directly affects cells. Using single-cell RNA sequencing, the scientists detected the transcripts from the TE in a specific cell population of the developing limb. With the help of the institute’s Microscopy Facility, they then visualized the resulting viral-like particles in the cells. “Our experiments show that the TE does not disrupt gene expression directly. Rather, it becomes part of a larger regulatory structure known as a topologically associated domain, or TAD. Within this domain, its activation leads to production of non-infectious viral particles that are toxic to the cell,” Juliane Glaser explains.
While previous studies have shown that transposable elements can produce viral particles in human cells in vitro, it remains unclear whether a similar mechanism contributes to disease in vivo, or how widespread such effects might be. Juliane Glaser will continue investigating the role of transposable elements in mammalian development in her own lab, which she recently established at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany. “One of the main questions my lab will explore is the physiological function of transposable elements in development, alongside their role in pathologies,” she says.
