X-Linked Dystonia-Parkinsonism (XDP) is an inherited disorder that primarily affects men with Filipino ancestry from Panay Island. The condition, which causes movement problems such as dystonia and parkinsonism, begins in adulthood. Patients experience everything from muscle cramps to slow movements, tremors, stiffness, and difficulties in daily activities like walking and speaking.
Earlier research in the field identified the insertion of a transposable element in the TAF1 gene as the cause of XDP. These transposable elements, also known as transposons or jumping genes, are DNA segments that can move around the genome and contribute to genetic diversity as they can be passed down through generations.
Vivien Horvath, a postdoctoral researcher in the Laboratory of Molecular Neurogenetics and first author of the study, explains, "Studies indicate that there may be a new transposon mobilization in one out of every twenty births, introducing unique genetic variations in the population." While they can contribute to genetic diversity, transposable elements can also cause diseases like XDP by inserting themselves into important genes and disrupting their function.
"Our goal was to understand how the insertion of the XDP-specific transposon affects the TAF1 gene and leads to the disease," notes Vivien. The study used neural stem cells obtained from patients with XDP and their healthy relatives. This approach provided a human cellular model closely mimicking patient conditions, allowing the team to observe the effects of epigenetic regulation in a relevant biological context.
"Our findings offer new insights into transposon control and their regulatory effects in the context of disease development," elaborates Vivien. “The insights gained provide a roadmap for future research into how our genes can be affected by these hidden elements, ultimately leading to different disorders.”
Using advanced techniques – CRISPRi, CUT&RUN, and Oxford Nanopore Sequencing- to modify gene expression and to look at long DNA sequences, researchers explored the repressive epigenetic mechanisms controlling transposons. They found that this epigenetic defense system recognizes the XDP transposon and also protects the TAF1 gene from its effect.
The study highlighted ZNF91, a protein important in regulating insertions similar to the one in XDP. This protein places special chemical tags, known as repressive epigenetic marks, like histone methylation and DNA methylation, around the transposon in the TAF1 gene. "When we removed these epigenetic marks, the misregulation of the TAF1 gene worsened. Based on these results we hypothesize that maintaining these marks is crucial for normal TAF1 gene expression," Vivien emphasizes.
Their findings suggest that changes or loss of these epigenetic marks during aging might be responsible for the adult onset of XDP symptoms. “What we think happens is that for the first part of a patient's life, that gene region is protected. Later, as these epigenetic marks change, the region is no longer protected, leading to the misregulation of gene expression,” explains Vivien.
Looking ahead, these findings could lead to new treatments. "One exciting possibility is developing a DNA methylation replacement therapy," says Vivien. "By maintaining these protective epigenetic marks throughout life, we may be able to prevent the onset or progression of XDP. But there is still much to learn before we get to that point."
