SINE-VNTR-Alu (SVA) elements are hominoid-specific transposons that have entered our genomes during the last few million years of evolution. Strikingly, some SVAs are still active and able to retrotranspose, significantly contributing to polymorphisms in the human population. Such polymorphic SVA alleles harbour gene-regulatory potential and can lead to genetic disease. One notable example is X-Linked Dystonia-Parkinsonism (XDP), a neurodegenerative disorder caused by an SVA insertion at the TAF1 locus. However, how these SVA insertions are controlled in the human brain and the function by which they impact human physiology and disease is unknown.

Here, we dissect the epigenetic regulation and influence of SVAs in various cellular models of X-Linked Dystonia-Parkinsonism. Employing a combination of CUT&RUN, Oxford Nanopore Sequencing and CRISPR approaches we demonstrate that the KRAB zinc finger protein ZNF91 orchestrates the establishment of H3K9me3 and DNA methylation over SVAs, including polymorphic ones, in a cell-type specific manner. The resulting mini-heterochromatin domains not only silence SVA expression but also mitigate their cis-regulatory impact, thereby safeguarding the human genome from their effect. Interestingly, this regulatory mechanism proves to be crucial for XDP pathology. Removal of H3K9me3 and DNA methylation in patient derived neural progenitor cells severely aggravates the XDP molecular phenotype, resulting in increased TAF1 intron retention and reduced expression. 

Our results provide unique mechanistic insights into how human polymorphic transposon insertions are recognized, and their regulatory impact constrained by an innate epigenetic defence system. Furthermore, XDP serves as a suitable model to highlight the importance of this system within the context of disease.