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

Autor: van den Boogaard M; Amsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam Cardiovascular Sciences, 1105AZ Amsterdam, the Netherlands., van Weerd JH; Amsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam Cardiovascular Sciences, 1105AZ Amsterdam, the Netherlands., Bawazeer AC; Amsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam Cardiovascular Sciences, 1105AZ Amsterdam, the Netherlands., Hooijkaas IB; Amsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam Cardiovascular Sciences, 1105AZ Amsterdam, the Netherlands., van de Werken HJG; 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., Tessadori F; Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands., de Laat W; Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands., Barnett P; Amsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam Cardiovascular Sciences, 1105AZ Amsterdam, the Netherlands., Bakkers J; Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands., Christoffels VM; Amsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam Cardiovascular Sciences, 1105AZ Amsterdam, the Netherlands. Electronic address: v.m.christoffels@amsterdamumc.nl.
Jazyk: angličtina
Zdroj: Cell reports [Cell Rep] 2019 Sep 03; Vol. 28 (10), pp. 2704-2714.e5.
DOI: 10.1016/j.celrep.2019.08.007
Abstrakt: The human ether-a-go-go-related gene KCNH2 encodes the voltage-gated potassium channel underlying I Kr , 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.
(Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: