Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia.
University of New South Wales, Sydney, Kensington, NSW 2052, Australia.
Cardiovasc Res. 2021 Aug 29;117(10):2216-2227. doi: 10.1093/cvr/cvaa280.
Cardiac electrical activity is extraordinarily robust. However, when it goes wrong it can have fatal consequences. Electrical activity in the heart is controlled by the carefully orchestrated activity of more than a dozen different ion conductances. While there is considerable variability in cardiac ion channel expression levels between individuals, studies in rodents have indicated that there are modules of ion channels whose expression co-vary. The aim of this study was to investigate whether meta-analytic co-expression analysis of large-scale gene expression datasets could identify modules of co-expressed cardiac ion channel genes in human hearts that are of functional importance.
Meta-analysis of 3653 public human RNA-seq datasets identified a strong correlation between expression of CACNA1C (L-type calcium current, ICaL) and KCNH2 (rapid delayed rectifier K+ current, IKr), which was also observed in human adult heart tissue samples. In silico modelling suggested that co-expression of CACNA1C and KCNH2 would limit the variability in action potential duration seen with variations in expression of ion channel genes and reduce susceptibility to early afterdepolarizations, a surrogate marker for proarrhythmia. We also found that levels of KCNH2 and CACNA1C expression are correlated in human-induced pluripotent stem cell-derived cardiac myocytes and the levels of CACNA1C and KCNH2 expression were inversely correlated with the magnitude of changes in repolarization duration following inhibition of IKr.
Meta-analytic approaches of multiple independent human gene expression datasets can be used to identify gene modules that are important for regulating heart function. Specifically, we have verified that there is co-expression of CACNA1C and KCNH2 ion channel genes in human heart tissue, and in silico analyses suggest that CACNA1C-KCNH2 co-expression increases the robustness of cardiac electrical activity.
心脏的电活动异常稳健。然而，一旦出现异常，就可能导致致命后果。心脏的电活动由十多种不同的离子电导精心协调控制。尽管个体之间的心脏离子通道表达水平存在相当大的差异，但啮齿动物的研究表明，存在一些离子通道表达共同变化的模块。本研究旨在探讨大规模基因表达数据集的元分析共表达分析是否可以识别人类心脏中具有功能重要性的共表达心脏离子通道基因模块。
对 3653 个公开的人类 RNA-seq 数据集进行元分析，确定 CACNA1C（L 型钙电流，ICaL）和 KCNH2（快速延迟整流钾电流，IKr）表达之间存在很强的相关性，在人类成年心脏组织样本中也观察到了这种相关性。计算机模拟表明，CACNA1C 和 KCNH2 的共表达将限制离子通道基因表达变化导致的动作电位持续时间的可变性，并降低早期后除极的易感性，早期后除极是心律失常的替代标志物。我们还发现，人类诱导多能干细胞衍生的心肌细胞中 KCNH2 和 CACNA1C 的表达水平相关，并且 CACNA1C 和 KCNH2 的表达水平与 IKr 抑制后复极持续时间变化幅度呈负相关。
使用多种独立的人类基因表达数据集的元分析方法可以用于识别对调节心脏功能很重要的基因模块。具体来说，我们已经验证了 CACNA1C 和 KCNH2 离子通道基因在人类心脏组织中存在共表达，并且计算机分析表明 CACNA1C-KCNH2 共表达增加了心脏电活动的稳健性。
