Amsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam Cardiovascular Sciences, 1105AZ Amsterdam, the Netherlands.
Cancer Computational Biology Center, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, the Netherlands; Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, the Netherlands; Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands.
Cell Rep. 2019 Sep 3;28(10):2704-2714.e5. doi: 10.1016/j.celrep.2019.08.007.
The human ether-a-go-go-related gene KCNH2 encodes the voltage-gated potassium channel underlying I, a current critical for the repolarization phase of the cardiac action potential. Mutations in KCNH2 that cause a reduction of the repolarizing current can result in cardiac arrhythmias associated with long-QT syndrome. Here, we investigate the regulation of KCNH2 and identify multiple active enhancers. A transcribed enhancer ∼85 kbp downstream of Kcnh2 physically contacts the promoters of two Kcnh2 isoforms in a cardiac-specific manner in vivo. Knockdown of its ncRNA transcript results in reduced expression of Kcnh2b and two neighboring mRNAs, Nos3 and Abcb8, in vitro. Genomic deletion of the enhancer, including the ncRNA transcription start site, from the mouse genome causes a modest downregulation of both Kcnh2a and Kcnh2b in the ventricles. These findings establish that the regulation of Kcnh2a and Kcnh2b is governed by a complex regulatory landscape that involves multiple partially redundantly acting enhancers.
人类醚-a--go-go 相关基因 KCNH2 编码电压门控钾通道，该通道是心肌动作电位复极化阶段的关键电流。导致复极化电流减少的 KCNH2 突变可导致与长 QT 综合征相关的心律失常。在这里，我们研究了 KCNH2 的调节，并确定了多个活跃的增强子。Kcnh2 下游约 85 kbp 的转录增强子在体内以心脏特异性的方式与两种 Kcnh2 同工型的启动子物理接触。其 ncRNA 转录本的敲低导致 Kcnh2b 和两个相邻的 mRNA（Nos3 和 Abcb8）在体外的表达减少。从鼠基因组中删除增强子（包括 ncRNA 转录起始位点）会导致心室中 Kcnh2a 和 Kcnh2b 的适度下调。这些发现表明，Kcnh2a 和 Kcnh2b 的调节受涉及多个部分冗余增强子的复杂调节景观控制。
