Studying disease-causing transposable element insertions using Oxford Nanopore sequencing | LC 25

Biography

Vivien Horvath completed her PhD in Biomedicine at Pompeu Fabra University, Barcelona. Currently, she is a senior postdoctoral researcher at Lund University/Lund Stem Cell Center. Her research focuses on the non-coding genome, particularly transposable elements, in aging and related neurodegenerative disorders. Vivien investigates how repetitive sequences and their epigenetic regulators, like DNA methylation, affect gene expression and disease progression, currently focusing on X-Linked dystonia-parkinsonism. In her research she uses nanopore sequencing to identify methylation patterns over transposable elements and to discover previously hidden non-coding insertions.

Abstract

X-Linked dystonia-parkinsonism (XDP) is an age-related neurodegenerative disorder caused by a polymorphic retrotransposon insertion belonging to the SINE-VNTR-Alu (SVA) family. This insertion was identified in the 32nd intron of the TAF1 gene. Using patient-derived cell models and Oxford Nanopore sequencing we previously showed that the XDP-SVA is covered by DNA methylation. CRISPR-mediated removal of this methylation exacerbated the molecular disease phenotype, suggesting a protective role. Since XDP is an adult-onset disease, we hypothesize that DNA methylation decreases with age, leading to disease manifestation. To understand how this process works in the brain, we sequenced post-mortem prefrontal cortex samples from XDP patients and control individuals using Oxford Nanopore sequencing to examine disease-related DNA methylation patterns. Our results indicate that the methylation over the XDP-SVA is altered in the brain of the patients, suggesting a connection between aging, reduced methylation, and disease onset. We are currently investigating the correlation between these methylation alterations and TAF1 gene expression to determine whether hypomethylation levels are linked to disease severity and onset. These findings underscore the pivotal role of age-related DNA methylation changes over retrotransposons in triggering neurodegenerative disorders and move the field forward towards translational research efforts.