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

Malou van den Boogaard; Jan Hendrik van Weerd; Amira C Bawazeer; Ingeborg B Hooijkaas; Harmen J G van de Werken; Federico Tessadori; Wouter de Laat; Phil Barnett; Jeroen Bakkers; Vincent M Christoffels

doi:10.1016/j.celrep.2019.08.007

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

Malou van den Boogaard, Jan Hendrik van Weerd, Amira C Bawazeer, Ingeborg B Hooijkaas, Harmen J G van de Werken, Federico Tessadori, Wouter de Laat, Phil Barnett, Jeroen Bakkers, Vincent M Christoffels

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

12 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2704-2714.e5
Journal	Cell Reports
Volume	28
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2019.08.007
Publication status	Published - 03 Sept 2019

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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. (2019). Identification and Characterization of a Transcribed Distal Enhancer Involved in Cardiac Kcnh2 Regulation. Cell Reports, 28(10), 2704-2714.e5. https://doi.org/10.1016/j.celrep.2019.08.007

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title = "Identification and Characterization of a Transcribed Distal Enhancer Involved in Cardiac Kcnh2 Regulation",

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.",

author = "{van den Boogaard}, Malou and {van Weerd}, {Jan Hendrik} and Bawazeer, {Amira C} and Hooijkaas, {Ingeborg B} and {van de Werken}, {Harmen J G} and Federico Tessadori and {de Laat}, Wouter and Phil Barnett and Jeroen Bakkers and Christoffels, {Vincent M}",

year = "2019",

month = sep,

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doi = "10.1016/j.celrep.2019.08.007",

language = "English",

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T1 - Identification and Characterization of a Transcribed Distal Enhancer Involved in Cardiac Kcnh2 Regulation

AU - van den Boogaard, Malou

AU - van Weerd, Jan Hendrik

AU - Bawazeer, Amira C

AU - Hooijkaas, Ingeborg B

AU - van de Werken, Harmen J G

AU - Tessadori, Federico

AU - de Laat, Wouter

AU - Barnett, Phil

AU - Bakkers, Jeroen

AU - Christoffels, Vincent M

PY - 2019/9/3

Y1 - 2019/9/3

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2019.08.007

DO - 10.1016/j.celrep.2019.08.007

M3 - Article

C2 - 31484079

SN - 2211-1247

VL - 28

SP - 2704-2714.e5

JO - Cell Reports

JF - Cell Reports

IS - 10

ER -

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

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