TBX5 drives Scn5a expression to regulate cardiac conduction system function
TBX5 drives Scn5a expression to regulate cardiac conduction system function
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DOI：
10.1172/jci62617
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发表时间：
2012-07-01
影响因子：
15.9
通讯作者：
Moskowitz, Ivan P.
中科院分区：
文献类型：
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作者：
Arnolds, David E.;Liu, Fang;Moskowitz, Ivan P.
心脏传导系统（CCS）疾病很常见，会导致传导中断和心律受损，发病率和死亡率很高。目前的治疗选择有限，开发基于细胞的再生疗法的合理努力需要了解建立和维持 CCS 功能的分子网络。最近的全基因组关联研究 (GWAS) 发现了许多与成人 CCS 功能相关的基因座，包括 TBX5 和 SCN5A。我们假设 TBX5 是一种关键的发育转录因子，调节成熟 CCS 功能所需的转录网络。我们发现，从成熟的小鼠心室传导系统（VCS）（包括房室束和束支）中删除 Tbx5，会导致严重的 VCS 功能后果，包括快速传导丧失、心律失常和猝死。在 VCS 特异性 Tbx5 敲除中，心室收缩功能和 VCS 命运图保持不变。然而，快速传导的关键介质，包括由 Scn5a 编码的 Na(v)1.5 和连接蛋白 40 (Cx40)，在 VCS 中表现出 Tbx5 依赖性表达。我们鉴定出 Scn5a 下游的 TBX5 响应增强子，足以驱动体内 VCS 表达，依赖于典型的 T 盒结合位点。我们的结果建立了 Tbx5 和 Scn5a 之间的直接分子联系，并阐明了影响成熟 VCS 功能的人类 GWAS 位点之间的层次结构，为理解 CCS 疾病的分子病理学建立了范例。
Cardiac conduction system (CCS) disease, which results in disrupted conduction and impaired cardiac rhythm, is common with significant morbidity and mortality. Current treatment options are limited, and rational efforts to develop cell-based and regenerative therapies require knowledge of the molecular networks that establish and maintain CCS function. Recent genome-wide association studies (GWAS) have identified numerous loci associated with adult human CCS function, including TBX5 and SCN5A. We hypothesized that TBX5, a critical developmental transcription factor, regulates transcriptional networks required for mature CCS function. We found that deletion of Tbx5 from the mature murine ventricular conduction system (VCS), including the AV bundle and bundle branches, resulted in severe VCS functional consequences, including loss of fast conduction, arrhythmias, and sudden death. Ventricular contractile function and the VCS fate map remained unchanged in VCS-specific Tbx5 knockouts. However, key mediators of fast conduction, including Na(v)1.5, which is encoded by Scn5a, and connexin 40 (Cx40), demonstrated Tbx5-dependent expression in the VCS. We identified a TBX5-responsive enhancer downstream of Scn5a sufficient to drive VCS expression in vivo, dependent on canonical T-box binding sites. Our results establish a direct molecular link between Tbx5 and Scn5a and elucidate a hierarchy between human GWAS loci that affects function of the mature VCS, establishing a paradigm for understanding the molecular pathology of CCS disease.