Large-scale Single-nuclei Profiling Identifies Role for ATRNL1 in Atrial Fibrillation [bulk RNA-seq]

Atrial fibrillation (AF) is the most common sustained arrhythmia in humans, yet the molecular basis of AF remains incompletely understood. To determine the cell type-specific transcriptional changes underlying AF, we performed single-nucleus RNA-seq (snRNA-seq) on age- and sex-matched left atrial (LA) samples from 18 patients with AF and 16 controls without AF. From more than 175,000 nuclei we identified 15 cell types but found that only cardiomyocytes (CMs) and macrophages (MΦs) had a significant number of differentially expressed genes in patients with AF. Attractin Like 1 (ATRNL1) was strongly overexpressed in CMs among patients with AF and localized to the intercalated discs. Further, in both knockdown and overexpression experiments in atrial human embryonic stem cell-derived CMs (hESC-aCMs) we identified a potent role for ATRNL1 in cell stress response, cardiac conduction, cell junction organization and in modulation of the cardiac action potential. Finally, we prioritized genes at the known genetic loci for AF and identified an unexpected expression for a leading AF candidate gene, KCNN3. In sum, we have identified a role for ATRNL1 and other differentially regulated genes that may serve as potential therapeutic targets for this common arrhythmia. To characterize the cellular and molecular characteristics associated with the gene ATRNL1 in atrial cardiomyocytes (CMs), we performed bulk RNA-seq on human embryonic stem cell derived atrial cardiomyocytes (hESC-aCMs) treated with siRNAs against ATRNL1, scramble control siRNAs, and lentiviruses for overexpressing the short isoform of ATRNL1.