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<p>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 (<i>N</i> = 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 <i>IFNG</i> locus (<i>LINC01479</i>, <i>IFNG-AS1</i>) 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月25日

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  • 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

摘要

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.