Identification and Characterization of a TranscribedDistal Enhancer Involved in Cardiac Kcnh2Regulation

Authors:
Malou van den Boogaard,Jan Hendrik van Weerd,Amira C. Bawazeer, ..., Phil Barnett,Jeroen Bakkers, Vincent M. Christoffels
In:
Source: Cell Rep
Publication Date: (2019)
Issue: 28: 2704-2714
Research Area:
Cardiovascular
Cells used in publication:
293T
Species: human
Tissue Origin: kidney
HL-1
Species: mouse
Tissue Origin: heart
Culture Media:
Experiment


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.