Large-scale single-nuclei profiling identifies role for ATRNL1 in atrial fibrillation

Nat Commun. 2024 Nov 19;15(1):10002. doi: 10.1038/s41467-024-54296-w.

Abstract

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 perform single-nucleus RNA-seq (snRNA-seq) on left atrial (LA) samples from patients with AF and controls. From more than 175,000 nuclei we find that only cardiomyocytes (CMs) and macrophages (MΦs) have a significant number of differentially expressed genes in patients with AF. Attractin Like 1 (ATRNL1) was overexpressed in CMs among patients with AF and localized to the intercalated disks. Further, in both knockdown and overexpression experiments we identify a potent role for ATRNL1 in cell stress response, and in the modulation of the cardiac action potential. Finally, we detect an unexpected expression pattern for a leading AF candidate gene, KCNN3. In sum, we uncover a role for ATRNL1 which may serve as potential therapeutic target for this common arrhythmia.

MeSH terms

  • Action Potentials
  • Animals
  • Atrial Fibrillation* / genetics
  • Atrial Fibrillation* / metabolism
  • Cell Nucleus / metabolism
  • Female
  • Gene Expression Profiling
  • Heart Atria / metabolism
  • Humans
  • Macrophages / metabolism
  • Male
  • Mice
  • Middle Aged
  • Myocytes, Cardiac* / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • RNA-Seq

Substances

  • RNA-Binding Proteins