BACKGROUND:The relationship between heart failure (HF) and atrial fibrillation (AF) is clear, with up to half of patients with HF progressing to AF. The pathophysiological basis of AF in the context of HF is presumed to result from atrial remodeling. Upregulation of the transcription factor FOG2 (friend of GATA2; encoded by ZFPM2) is observed in human ventricles during HF and causes HF in mice.METHODS:FOG2 expression was assessed in human atria. The effect of adult-specific FOG2 overexpression in the mouse heart was evaluated by whole animal electrophysiology, in vivo organ electrophysiology, cellular electrophysiology, calcium flux, mouse genetic interactions, gene expression, and genomic function, including a novel approach for defining functional transcription factor interactions based on overlapping effects on enhancer noncoding transcription.RESULTS:FOG2 is significantly upregulated in the human atria during HF. Adult cardiomyocyte-specific FOG2 overexpression in mice caused primary spontaneous AF before the development of HF or atrial remodeling. FOG2 overexpression generated arrhythmia substrate and trigger in cardiomyocytes, including calcium cycling defects. We found that FOG2 repressed atrial gene expression promoted by TBX5. FOG2 bound a subset of GATA4 and TBX5 co-bound genomic locations, defining a shared atrial gene regulatory network. FOG2 repressed TBX5-dependent transcription from a subset of co-bound enhancers, including a conserved enhancer at the Atp2a2 locus. Atrial rhythm abnormalities in mice caused by Tbx5 haploinsufficiency were rescued by Zfpm2 haploinsufficiency.CONCLUSIONS:Transcriptional changes in the atria observed in human HF directly antagonize the atrial rhythm gene regulatory network, providing a genomic link between HF and AF risk independent of atrial remodeling.

中文翻译：

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从心力衰竭到房颤风险的基因组联系：FOG2 调节 TBX5/GATA4 依赖的心房基因调控网络

背景：心力衰竭（HF）和心房颤动（AF）之间的关系是明确的，多达一半的心力衰竭患者会进展为房颤。 HF 背景下 AF 的病理生理学基础被认为是由心房重塑引起的。在心力衰竭期间，在人心室中观察到转录因子 FOG2（GATA2 的朋友；由ZFPM2编码）的上调，并导致小鼠心力衰竭。方法：评估人心房中的 FOG2 表达。通过整体动物电生理学、体内器官电生理学、细胞电生理学、钙通量、小鼠遗传相互作用、基因表达和基因组功能（包括定义功能转录因子的新方法）评估成人特异性 FOG2 过表达在小鼠心脏中的影响基于对增强子非编码转录的重叠效应的相互作用。结果：心力衰竭期间，FOG2 在人类心房中显着上调。小鼠中成人心肌细胞特异性 FOG2 过度表达导致原发性自发性房颤，然后发生心力衰竭或心房重塑。 FOG2 过度表达会在心肌细胞中产生心律失常底物和触发因素，包括钙循环缺陷。我们发现 FOG2 抑制 TBX5 促进的心房基因表达。 FOG2 结合了 GATA4 和 TBX5 共结合基因组位置的子集，定义了共享的心房基因调控网络。 FOG2 抑制来自共结合增强子子集的 TBX5 依赖性转录，包括Atp2a2基因座的保守增强子。由Tbx5单倍体不足引起的小鼠心房节律异常可通过Zfpm2单倍体不足得到挽救。 结论：在人类心力衰竭中观察到的心房转录变化直接拮抗心房节律基因调控网络，提供了心力衰竭和房颤风险之间独立于心房重构的基因组联系。