Postdoctoral Researcher Lund University Lund, Sweden
Abstract: X-Linked Dystonia-Parkinsonism (XDP) is an adult-onset neurodegenerative disorder. Recently, a polymorphic transposable element (TE) insertion in the 32nd intron of the TAF1 gene has been identified as the genetic factor responsible for this disease. The XDP-TE is associated with TAF1 mis-regulation, but the mechanisms behind this phenomenon remain elusive. We hypothesize that repressive epigenetic marks on the XDP-TE are key players in this process. Thus, here we aim to dissect the molecular intricacies that keep the XDP-TE at bay and identify how it triggers aberrant TAF1 expression, ultimately leading to XDP. To do so we used XDP patient-derived iPSCs, neural progenitor cells and post-mortem brain tissue. To understand the epigenetic regulators controlling this insertion we employed CUT&RUN and Oxford Nanopore Sequencing. Moreover, to illuminate what factors establish these marks and their effect on gene expression, we did CRISPR inhibition of various candidate genes coupled with RNA sequencing. Using our patient-derived cellular models we demonstrate that ZNF91 - a TE-binding KRAB-Zinc Finger Protein - establishes H3K9me3 and DNA methylation over the XDP-TE in a cell type specific manner. Interestingly, removal of these epigenetic repressors severely aggravates the XDP molecular phenotype, causing a reduced TAF1 expression and increased intron retention. In line with this, our preliminary findings from patient-derived post-mortem brain tissues reveal hypomethylation of the XDP-TE in the brain of affected individuals, coupled with high levels of the pathogenic intron retention. Given that XDP is an adult-onset disorder, these results suggest that age-related loss of DNA methylation may play a critical role in driving disease progression. Our study unveils how a polymorphic TE results in XDP and highlights DNA methylation as potential therapeutic target. Moreover, this work underscores the significance of studying polymorphic TEs as disease triggers, with implications for various disorders.
