A common genetic variant within SCN10A modulates cardiac SCN5A expression
Malou van den Boogaard, … , Phil Barnett, Ivan P. Moskowitz
Malou van den Boogaard, … , Phil Barnett, Ivan P. Moskowitz
Published March 18, 2014
Citation Information: J Clin Invest. 2014;124(4):1844-1852. https://doi.org/10.1172/JCI73140.
View: Text | PDF
Research Article

A common genetic variant within SCN10A modulates cardiac SCN5A expression

Abstract

Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel–encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.

Authors

Malou van den Boogaard, Scott Smemo, Ozanna Burnicka-Turek, David E. Arnolds, Harmen J.G. van de Werken, Petra Klous, David McKean, Jochen D. Muehlschlegel, Julia Moosmann, Okan Toka, Xinan H. Yang, Tamara T. Koopmann, Michiel E. Adriaens, Connie R. Bezzina, Wouter de Laat, Christine Seidman, J.G. Seidman, Vincent M. Christoffels, Marcelo A. Nobrega, Phil Barnett, Ivan P. Moskowitz

×

Figure 1

Contact profiles of enhancers and promoters of the Scn10a-Scn5a locus in combination with ChIP-seq data.

Options: View larger image (or click on image) Download as PowerPoint
Contact profiles of enhancers and promoters of the Scn10a-Scn5a locus in...
(A) UCSC genome browser view of chr3:38,465,426–38,861,154 (hg18), demonstrating distinct LD blocks within the SCN10A-SCN5A locus with SNPs tagged in GWAS studies (green) (1–9). (B) Mouse region (mm9; chr9:119,303,698–119,662,489) depicted with 4C analysis showing contact profiles of EnhA in Scn10a (blue), Scn5a promoter C (green), and EnhB downstream of Scn5a (red). Blue, green, and red arrows correspond to the position of the different viewpoints. Black arrows represent the position of the promoter of Scn10a and alternate promoters of Scn5a (promoters A and B). From the EnhA viewpoint, interactions can be observed between EnhA, EnhB, and the Scn5a promoter regions. From the Scn5a promoter C viewpoint, contacts can be observed with EnhA and EnhB and weakly with the Scn10a promoter region. From EnhB, contacts with the Scn5a promoter region and, weakly, with EnhA can be seen. See Supplemental Figure 1 for quantitative assessment of these interactions. (C) UCSC genome browser views of ChIP-seq data of the TBX3 (21) and of Pol2 and p300 (27–29) binding profiles aligned with the 4C traces, showing the correspondence between contacts and factor occupancy. (D) Model for the interactions of EnhA (blue) and EnhB (red) with the Scn5a and Scn10a promoters (green and gray, respectively). The promoter of flanking gene Exog does not interact.