Co-expression of calcium channels and delayed rectifier potassium channels protects the heart from proarrhythmic events [Figure 2 mRNA data]

Analysis of rhythmonome gene expression in cardiac myocytes derived from human induced pluripotent stem cells Cardiac electrical activity is controlled by the carefully orchestrated activity of more than a dozen different ion conductances. Yet, there is considerable variability in cardiac ion channel expression levels both within and between subjects. In this study we tested the hypothesis that variations in ion channel expression between individuals are not random but rather there are modules of co-expressed genes and that these modules make electrical signaling in the heart more robust. Meta-analysis of 3653 public 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 verified in mRNA extracted from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). In silico modeling, validated with functional measurements in hiPSC-CM, indicates that the co-expression of CACNA1C and KCNH2 limits the variability in action potential duration and reduces susceptibility to early afterdepolarizations, a surrogate marker for pro-arrhythmia. 10 samples derived from iPS cells derived from 10 control subjects. Total RNA was obtained from 40,000 hiPSC-CMs lysed using QIAzol Lysis reagent (Qiagen). The RNA was purified using miRNeasy® Mini Kit (Qiagen), and all samples had RIN values >7.5, and were analysed using Agilent Bioanalyzer pico-chip. RNA samples were hybridised with probes designed to detect 35 known rhythmonome genes using nCounter (NanoString Technologies)