An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo

Joyce C K Man; Rajiv A Mohan; Malou van den Boogaard; Catharina R E Hilvering; Catherine Jenkins; Vincent Wakker; Valerio Bianchi; Wouter de Laat; Phil Barnett; Bastiaan J Boukens; Vincent M Christoffels

doi:10.1038/s41467-019-12856-5

An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo

Joyce C K Man, Rajiv A Mohan, Malou van den Boogaard, Catharina R E Hilvering, Catherine Jenkins, Vincent Wakker, Valerio Bianchi, Wouter de Laat, Phil Barnett, Bastiaan J Boukens, Vincent M Christoffels

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

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Mutations and variations in and around SCN5A, encoding the major cardiac sodium channel, influence impulse conduction and are associated with a broad spectrum of arrhythmia disorders. Here, we identify an evolutionary conserved regulatory cluster with super enhancer characteristics downstream of SCN5A, which drives localized cardiac expression and contains conduction velocity-associated variants. We use genome editing to create a series of deletions in the mouse genome and show that the enhancer cluster controls the conformation of a >0.5 Mb genomic region harboring multiple interacting gene promoters and enhancers. We find that this cluster and its individual components are selectively required for cardiac Scn5a expression, normal cardiac conduction and normal embryonic development. Our studies reveal physiological roles of an enhancer cluster in the SCN5A-SCN10A locus, show that it controls the chromatin architecture of the locus and Scn5a expression, and suggest that genetic variants affecting its activity may influence cardiac function.

Originele taal-2	Engels
Pagina's (van-tot)	4943
Tijdschrift	Nature Communications
Volume	10
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1038/s41467-019-12856-5
Status	Gepubliceerd - 30 okt. 2019

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10.1038/s41467-019-12856-5

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abstract = "Mutations and variations in and around SCN5A, encoding the major cardiac sodium channel, influence impulse conduction and are associated with a broad spectrum of arrhythmia disorders. Here, we identify an evolutionary conserved regulatory cluster with super enhancer characteristics downstream of SCN5A, which drives localized cardiac expression and contains conduction velocity-associated variants. We use genome editing to create a series of deletions in the mouse genome and show that the enhancer cluster controls the conformation of a >0.5 Mb genomic region harboring multiple interacting gene promoters and enhancers. We find that this cluster and its individual components are selectively required for cardiac Scn5a expression, normal cardiac conduction and normal embryonic development. Our studies reveal physiological roles of an enhancer cluster in the SCN5A-SCN10A locus, show that it controls the chromatin architecture of the locus and Scn5a expression, and suggest that genetic variants affecting its activity may influence cardiac function.",

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AU - Boogaard, Malou van den

AU - Hilvering, Catharina R E

AU - Jenkins, Catherine

AU - Wakker, Vincent

AU - Bianchi, Valerio

AU - Laat, Wouter de

AU - Barnett, Phil

AU - Boukens, Bastiaan J

AU - Christoffels, Vincent M

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AB - Mutations and variations in and around SCN5A, encoding the major cardiac sodium channel, influence impulse conduction and are associated with a broad spectrum of arrhythmia disorders. Here, we identify an evolutionary conserved regulatory cluster with super enhancer characteristics downstream of SCN5A, which drives localized cardiac expression and contains conduction velocity-associated variants. We use genome editing to create a series of deletions in the mouse genome and show that the enhancer cluster controls the conformation of a >0.5 Mb genomic region harboring multiple interacting gene promoters and enhancers. We find that this cluster and its individual components are selectively required for cardiac Scn5a expression, normal cardiac conduction and normal embryonic development. Our studies reveal physiological roles of an enhancer cluster in the SCN5A-SCN10A locus, show that it controls the chromatin architecture of the locus and Scn5a expression, and suggest that genetic variants affecting its activity may influence cardiac function.

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An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo

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