Identification and Characterization of a Transcribed Distal Enhancer Involved in Cardiac Kcnh2 Regulation
Summary: 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 ass...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-09-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471931040X |
| _version_ | 1818175826751913984 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Malou van den Boogaard |
| collection | DOAJ |
| description | Summary: 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. : KCNH2 encodes a potassium channel critical for cardiac repolarization. Van den Boogaard et al. identified a transcribed cardiac-specific enhancer physically contacting Kcnh2. Genomic deletion by CRISPR/Cas9 caused a modest decrease in ventricular Kcnh2a and Kcnh2b expression, demonstrating the complexity of the regulatory landscape regulating Kcnh2 expression. Keywords: Kcnh2, hERG, LQTS, enhancer, transcriptional regulation, regulatory element, CRISPR genome editing, chromatin conformation, ncRNA |
| first_indexed | 2024-12-11T20:06:28Z |
| format | Article |
| id | doaj.art-f23e46c627da422ab766f3b9dde3a0a8 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T20:06:28Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-f23e46c627da422ab766f3b9dde3a0a82022-12-22T00:52:24ZengElsevierCell Reports2211-12472019-09-01281027042714.e5Identification and Characterization of a Transcribed Distal Enhancer Involved in Cardiac Kcnh2 RegulationMalou van den Boogaard0Jan Hendrik van Weerd1Amira C. Bawazeer2Ingeborg B. Hooijkaas3Harmen J.G. van de Werken4Federico Tessadori5Wouter de Laat6Phil Barnett7Jeroen Bakkers8Vincent M. Christoffels9Amsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam Cardiovascular Sciences, 1105AZ Amsterdam, the NetherlandsAmsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam Cardiovascular Sciences, 1105AZ Amsterdam, the NetherlandsAmsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam Cardiovascular Sciences, 1105AZ Amsterdam, the NetherlandsAmsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam Cardiovascular Sciences, 1105AZ Amsterdam, the NetherlandsCancer 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 NetherlandsHubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the NetherlandsHubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the NetherlandsAmsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam Cardiovascular Sciences, 1105AZ Amsterdam, the NetherlandsHubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the NetherlandsAmsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam Cardiovascular Sciences, 1105AZ Amsterdam, the Netherlands; Corresponding authorSummary: 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. : KCNH2 encodes a potassium channel critical for cardiac repolarization. Van den Boogaard et al. identified a transcribed cardiac-specific enhancer physically contacting Kcnh2. Genomic deletion by CRISPR/Cas9 caused a modest decrease in ventricular Kcnh2a and Kcnh2b expression, demonstrating the complexity of the regulatory landscape regulating Kcnh2 expression. Keywords: Kcnh2, hERG, LQTS, enhancer, transcriptional regulation, regulatory element, CRISPR genome editing, chromatin conformation, ncRNAhttp://www.sciencedirect.com/science/article/pii/S221112471931040X |
| spellingShingle | 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 Identification and Characterization of a Transcribed Distal Enhancer Involved in Cardiac Kcnh2 Regulation Cell Reports |
| title | Identification and Characterization of a Transcribed Distal Enhancer Involved in Cardiac Kcnh2 Regulation |
| title_full | Identification and Characterization of a Transcribed Distal Enhancer Involved in Cardiac Kcnh2 Regulation |
| title_fullStr | Identification and Characterization of a Transcribed Distal Enhancer Involved in Cardiac Kcnh2 Regulation |
| title_full_unstemmed | Identification and Characterization of a Transcribed Distal Enhancer Involved in Cardiac Kcnh2 Regulation |
| title_short | Identification and Characterization of a Transcribed Distal Enhancer Involved in Cardiac Kcnh2 Regulation |
| title_sort | identification and characterization of a transcribed distal enhancer involved in cardiac kcnh2 regulation |
| url | http://www.sciencedirect.com/science/article/pii/S221112471931040X |
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