Cardiovascular Disease Initiative & Precision Cardiology Laboratory, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Nat Commun. 2024 Nov 19;15(1):10002. doi: 10.1038/s41467-024-54296-w.
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.
心房颤动（AF）是人类最常见的持续性心律失常，但 AF 的分子基础仍不完全清楚。为了确定 AF 背后的细胞类型特异性转录变化，我们对 AF 患者和对照的左心房（LA）样本进行了单细胞 RNA 测序（snRNA-seq）。在超过 175,000 个核中，我们发现只有心肌细胞（CMs）和巨噬细胞（MΦs）在 AF 患者中有大量差异表达的基因。在 AF 患者的 CMs 中，Attractin Like 1（ATRNL1）表达过度，定位于闰盘。此外，在敲低和过表达实验中，我们确定了 ATRNL1 在细胞应激反应和心脏动作电位调节中的重要作用。最后，我们检测到一个主要的 AF 候选基因 KCNN3 的意外表达模式。总之，我们揭示了 ATRNL1 的作用，它可能成为这种常见心律失常的潜在治疗靶点。
