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 (Human biologist); Pérez-Villa, Félix; Zimmer, Thomas (Biochemistry); Garcia-Bassets, Ivan; Brugada, Ramon; Beltran-Alvarez, Pedro; Pagans, Sara

School of Biological, Biomedical and Environmental Sciences
SCN5A; Transcriptional regulation; GATA4; GATA5; GATA6; Cardiac arrhythmias
2017

Journal article


Rights
©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/
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.

Publisher
The University of Hull
Peer reviewed
Yes
Language
English
Extent
2 MB
Identifier
hull:13975

Journal

Journal title
Journal of molecular and cellular cardiology
Publication date
2017
Publisher
Elsevier
DOI
10.1016/j.yjmcc.2016.10.013
ISSN (Print)
0022-2828
ISSN (Electronic)
1095-8584
Volume
102
Start page
74
End page
82
Notes

Authors' accepted manuscript of article published in: Journal of molecular and cellular cardiology, 2017, v.102.

Link
Published article
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