Single-nucleus multi-omics implicates androgen receptor signaling in cardiomyocytes and NR4A1 regulation in fibroblasts during atrial fibrillation

Francis J. A. Leblanc, Chi Him Kendrick Yiu, Lucia M. Moreira, Aaron M. Johnston, Neelam Mehta, Antonios Kourliouros, Rana Sayeed, Stanley Nattel, Svetlana Reilly, Guillaume Lettre

Abstract: The dysregulation of gene expression programs in the human atria during persistent atrial fibrillation (AF) is not completely understood. Here, we reanalyze bulk RNA-sequencing datasets from two studies (N = 242) and identified 755 differentially expressed genes in left atrial appendages of individuals with persistent AF and non-AF controls. We combined the bulk RNA-sequencing differentially expressed genes with a left atrial appendage single-nucleus multi-omics dataset to assign genes to specific atrial cell types. We found noncoding genes at the IFNG locus (LINC01479, IFNG-AS1) strongly dysregulated in cardiomyocytes. We defined a gene expression signature potentially driven by androgen receptor signaling in cardiomyocytes from individuals with AF. Cell-type-specific gene expression modules suggested an increase in T cell and a decrease in adipocyte and neuronal cell gene expression in AF. Lastly, we showed that reducing NR4A1 expression, a marker of a poorly characterized human atrial fibroblast subtype, fibroblast activation markers, extracellular matrix remodeling and cell proliferation decreased. By analyzing bulk and single-cell RNA-sequencing datasets generated from left atrial appendages of individuals with atrial fibrillation and non-affected controls, Leblanc and Yiu identify cell-type-specific genes and transcriptomic programs implicated in atrial fibrillation, a cardiomyocyte-specific androgen receptor signaling signature and an anti-fibrotic effect of NR4A1 inhibition in atrial cardiofibroblasts.

External IDs:doi:10.1038/s44161-025-00626-0