Genomic structure, transcriptional control, and tissue distribution of HERG1 and KCNQ1 genes.
The long QT syndrome genes human ether-a-go-go-related gene (HERG1) and voltage-gated K+ channel, KQT-like subfamily, member 1, gene (KCNQ1), encoding K+ channels critical to the repolarization rate and repolarization reserve in cardiac cells, and thereby the likelihood of arrhythmias, are both composed of two isoforms: HERG1a and HERG1b and KCNQ1a and KCNQ1b, respectively. Expression of these genes is dynamic, depending on the differentiation status and disease states. We identified their core promoter regions and transcription start sites. Our data suggest that HERG1a and HERG1b, and KCNQ1a and KCNQ1b, represent independent transcripts instead of being alternatively spliced variants of the same gene, for they each have their own transcription start sites and their own promoter regions. We obtained data pointing to the potential role of stimulating protein 1 (Sp1) in the transactivation of these genes. We compared expression profiling of these genes across a variety of human tissues. Consistent with the general lack of cis elements for cardiac-specific transcription factors and the presence of multiple sites for ubiquitous Sp1 sites in the core promoter regions of HERG1a/HERG1b and KCNQ1a/KCNQ1b genes, the transcripts demonstrated widespread distribution across a variety of human tissues. We further revealed that the mRNA levels of all HERG1 and KCNQ1 isoforms were asymmetrically distributed within the heart, being more abundant in the right atria and ventricles relative to the left atria and ventricles. These findings open up an opportunity for studying interventricular gradients of slow and rapid delayed rectifier K+ current and of cardiac repolarization as well. Our study might help us understand the molecular mechanisms for arrhythmias since heterogeneity of ion channel activities is an important substrate for arrhythmogenesis.
Luo
Xiaobin
X
Research Center, Montreal Heart Institute, University of Montreal, Montreal, PQ, Canada H1T 1C8.
Xiao
Jiening
J
Lin
Huixian
H
Lu
Yanjie
Y
Yang
Baofeng
B
Wang
Zhiguo
Z
D024506:5' Flanking Region / Q000235:genetics; D001483:Base Sequence; D002478:Cells, Cultured; D018899:CpG Islands / Q000235:genetics; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism; D023282:Nuclease Protection Assays; D010957:Plasmids / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution; D014162:Transfection
D018076:DNA, Complementary; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D012333:RNA, Messenger; D008156:Luciferases