A reduced TBX5-dependent gene regulatory network links atrial fibrillation and heart failure [Micro-C]
Atrial fibrillation (AF) and heart failure (HF) frequently co-occur and exacerbate each other's morbidity, yet the underlying molecular mechanisms remain incompletely understood. Here, we compared atrial gene regulatory networks across multiple mouse models of AF (Tbx5 cKO, Zfhx3 KO, Scn1b-null) and HF (TAC, AngII), revealing unexpected transcriptional and genomic convergence between Tbx5 cKO and HF models. Notably, Tbx5 was significantly downregulated in atrial tissue from both murine and human HF samples. We identified over 100 coordinately dysregulated Tbx5- and TAC-dependent transcription factor genes, with cell-type resolution achieved through single-cell transcriptomics. Loss of a TBX5-driven cardiomyocyte gene regulatory network—including Klf15, a transcriptional repressor of hypertrophy—was observed in both AF and HF models, while a shared disease-specific network emerged in activated fibroblasts, notably involving the pro-fibrotic regulator Sox9. These findings define a conserved TBX5-dependent atrial genomic injury response that may underlie the reciprocal pathophysiological relationship between AF and HF. Overall design: Micro-C performed on untreated HL1 cells