Journal Article

Genome writing to dissect consequences of SVA retrotransposon disease X-Linked Dystonia Parkinsonism

Rahman, Neha, Bragg, D Cristopher, Zhao, Yu, Appleby, Heather L, Jiang, Qingwen, Capponi, Simona, Limberg, Kerry C, Wadghiri, Youssef Z, Vaine, Christine A, Markovic, Stefan, Barriball, Kelly, Kim, Sang Yong, Timmers, H T Marc, Prakash, Priya, Wudzinska, Aleksandra M, Maurano, Matthew T, Boeke, Jef D, Zhang, Weimin, Ellis, Gwen, Brosh, Ran, Liddelow, Shane A, Mishkit, Orin

2025

Overview

Human retrotransposon insertions are often associated with diseases. In the case of the neurodegenerative X-Linked Dystonia-Parkinsonism disease, a human-specific SINE-VNTR- subfamily F retrotransposon was inserted in intron 32 of the gene. Here, we genomically rewrote a portion of the mouse allele with the corresponding 78-kb XDP patient derived allele. In mESCs, the presence of the intronic SVAs-rather than the hybrid gene structure-reduces hy levels. This leads to transcriptional downregulation of genes with TATA box enriched in their promoters and triggering apoptosis. Chromatin and transcriptome profiling revealed that intronic SVAs are actively transcribed, forming barriers that likely impede transcription elongation. In mice, neuronal lineage humanization resulted lethality of male progeny within two months. XDP male mice had severe atrophy centered on the striatum-the same affected brain region in XDP patients. Lastly, CRISPRa-mediated activation of hy restored mESC viability, suggesting boosting transcription as a therapeutic approach.