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 and Vincent M. Christoffels ()
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Joyce C. K. Man: Amsterdam Cardiovascular Sciences, Academic Medical Center
Rajiv A. Mohan: Amsterdam Cardiovascular Sciences, Academic Medical Center
Malou van den Boogaard: Amsterdam Cardiovascular Sciences, Academic Medical Center
Catharina R. E. Hilvering: Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht
Catherine Jenkins: Amsterdam Cardiovascular Sciences, Academic Medical Center
Vincent Wakker: Amsterdam Cardiovascular Sciences, Academic Medical Center
Valerio Bianchi: Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht
Wouter de Laat: Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht
Phil Barnett: Amsterdam Cardiovascular Sciences, Academic Medical Center
Bastiaan J. Boukens: Amsterdam Cardiovascular Sciences, Academic Medical Center
Vincent M. Christoffels: Amsterdam Cardiovascular Sciences, Academic Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12856-5

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