PUBLICATION

Identification and Characterization of a Transcribed Distal Enhancer Involved in Cardiac Kcnh2 Regulation

Authors
van den Boogaard, M., van Weerd, J.H., Bawazeer, A.C., Hooijkaas, I.B., van de Werken, H.J.G., Tessadori, F., de Laat, W., Barnett, P., Bakkers, J., Christoffels, V.M.
ID
ZDB-PUB-201002-232
Date
2019
Source
Cell Reports   28: 2704-2714.e5 (Journal)
Registered Authors
Bakkers, Jeroen
Keywords
CRISPR genome editing, Kcnh2, LQTS, chromatin conformation, enhancer, hERG, ncRNA, regulatory element, transcriptional regulation
MeSH Terms
  • Animals
  • CRISPR-Cas Systems/genetics
  • Cell Line
  • ERG1 Potassium Channel/genetics*
  • ERG1 Potassium Channel/metabolism
  • Enhancer Elements, Genetic/genetics*
  • Female
  • Gene Expression Regulation*
  • Genetic Loci
  • Heart Ventricles/metabolism
  • Humans
  • Myocardium/metabolism*
  • Promoter Regions, Genetic/genetics
  • Protein Isoforms/genetics
  • Protein Isoforms/metabolism
  • RNA, Untranslated/genetics
  • RNA, Untranslated/metabolism
  • Sequence Deletion
  • Transcription, Genetic*
  • Zebrafish
PubMed
31484079 Full text @ Cell Rep.
Abstract
The human ether-a-go-go-related gene KCNH2 encodes the voltage-gated potassium channel underlying IKr, 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.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping