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Transcriptional regulation of the sodium channel gene (SCN5A) by GATA4 in human heart

Tarradas, Anna; Pinsach-Abuin, Mel·lina; Mackintosh, Carlos; Llorà-Batlle, Oriol; Pérez-Serra, Alexandra; Batlle, Montserrat; Pérez-Villa, Félix; Zimmer, Thomas; Garcia-Bassets, Ivan; Brugada, Ramon; Beltran-Alvarez, Pedro; Pagans, Sara


Anna Tarradas

Mel·lina Pinsach-Abuin

Carlos Mackintosh

Oriol Llorà-Batlle

Alexandra Pérez-Serra

Montserrat Batlle

Félix Pérez-Villa

Thomas Zimmer

Ivan Garcia-Bassets

Ramon Brugada

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Dr Pedro Beltran-Alvarez
Senior Lecturer in Health and Climate Change and Programme co-Director of the MSc Health and Climate Change

Sara Pagans


Aberrant expression of the sodium channel gene (SCN5A) has been proposed to disrupt cardiac action potential and cause human cardiac arrhythmias, but the mechanisms of SCN5A gene regulation and dysregulation still remain largely unexplored. To gain insight into the transcriptional regulatory networks of SCN5A, we surveyed the promoter and first intronic regions of the SCN5A gene, predicting the presence of several binding sites for GATA transcription factors (TFs). Consistent with this prediction, chromatin immunoprecipitation (ChIP) and sequential ChIP (Re-ChIP) assays show co-occupancy of cardiac GATA TFs GATA4 and GATA5 on promoter and intron 1 SCN5A regions in freshfrozen human left ventricle samples. Gene reporter experiments show GATA4 and GATA5 synergism in the activation of the SCN5A promoter, and its dependence on predicted GATA binding sites. GATA4 and GATA6 mRNAs are robustly expressed in fresh-frozen human left ventricle samples as measured by highly sensitive droplet digital PCR (ddPCR). GATA5 mRNA is marginally but still clearly detected in the same samples. Importantly, GATA4 mRNA levels are strongly and positively correlated with SCN5A transcript levels in the human heart. Together, our findings uncover a novel mechanism of GATA TFs in the regulation of the SCN5A gene in human heart tissue. Our studies suggest that GATA5 but especially GATA4 are main contributors to SCN5A gene expression, thus providing a new paradigm of SCN5A expression regulation that may shed new light into the understanding of cardiac disease.


Tarradas, A., Pinsach-Abuin, M., Mackintosh, C., Llorà-Batlle, O., Pérez-Serra, A., Batlle, M., …Pagans, S. (2017). Transcriptional regulation of the sodium channel gene (SCN5A) by GATA4 in human heart. Journal of Molecular and Cellular Cardiology, 102, 74-82.

Journal Article Type Article
Acceptance Date Oct 24, 2016
Online Publication Date Nov 26, 2016
Publication Date Jan 1, 2017
Deposit Date Jul 9, 2018
Publicly Available Date Jul 12, 2018
Journal Journal of Molecular and Cellular Cardiology
Print ISSN 0022-2828
Electronic ISSN 1095-8584
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 102
Pages 74-82
Keywords SCN5A; Transcriptional regulation; GATA4; GATA5; GATA6; Cardiac arrhythmias
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