TOP1MT rs2293925 is a regulatory SNP with enhancer function that shapes mitochondrial R-Loop dynamics

Perturbed mtDNA maintenance and RNA metabolism are implicated in neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), which is characterized by mitochondrial impairment. Here we show that the common TOP1MT variant rs2293925 (R525W) has enhancer-like activity and associates with increased mitochondrial R-loops (RNA:DNA hybrids) in ALS-relevant contexts.

Tissue-dependent expression quantitative trait locus analysis, chromatin state annotation, reporter assays, and allele-specific DNA–protein binding assays support a transcriptional regulatory role for rs2293925. In isogenic cell models, the rs2293925-linked allele increased TOP1MT mRNA and protein abundance and was accompanied by increased mitochondrial R-loop signal. Enhanced mitochondrial R-loop formation was also observed in a pilot cohort of sporadic ALS samples carrying rs2293925 and in a neural lineage model using neural stem cells derived from C9orf72-positive ALS patients.