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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

Authors

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

Sara Pagans



Abstract

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.

Journal Article Type Article
Publication Date Jan 1, 2017
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
APA6 Citation 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. doi:10.1016/j.yjmcc.2016.10.013
DOI https://doi.org/10.1016/j.yjmcc.2016.10.013
Keywords SCN5A; Transcriptional regulation; GATA4; GATA5; GATA6; Cardiac arrhythmias
Publisher URL http://www.jmmc-online.com/article/S0022-2828%2816%2930389-3/fulltext
Copyright Statement ©2017, Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Additional Information This article is maintained by: Elsevier; Article Title: Transcriptional regulation of the sodium channel gene (SCN5A) by GATA4 in human heart; Journal Title: Journal of Molecular and Cellular Cardiology; CrossRef DOI link to publisher maintained version: http://dx.doi.org/10.1016/j.yjmcc.2016.10.013; Content Type: article; Copyright: © 2017 The Authors. Published by Elsevier Ltd.

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Copyright Statement
©2017, Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/



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