Regulation of SCN5A by microRNAs: miR-219 modulates SCN5A transcript expression and the effects of flecainide intoxication in mice

Daimi, Houria; Lozano-Velasco, Estefanía; Khelil, A.; Chibani, Jemni B.E.; Barana, Adriana; Amorós, Irene; Fuente, Marta González de la; Caballero, Ricardo; Aránega, Amelia; Franco, Diego

doi:10.1016/j.hrthm.2015.02.018

Cited by 39 publications

(35 citation statements)

References 27 publications

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“…Previous studies have demonstrated that SCN5A is under regulatory control by miRs targeting the 3′-UTR (22)(23)(24); however, our studies are the first to our knowledge to evaluate miR binding within the coding sequence, an often overlooked region in miR-related investigations. Indeed, our previous HITS-CLIP data revealed that the most prominent human cardiac Ago2 binding site within SCN5A lay within the terminal coding exon.…”

Section: Discussionmentioning

confidence: 88%

“…The clear relevance of SCN5A to arrhythmias has fueled vigorous research of cellular mechanisms controlling Na V 1.5 biosynthesis, posttranslational processing, localization, and function (18)(19)(20). Among these efforts, researchers have identified alternatively spliced SCN5A transcript isoforms that associate with fatal arrhythmias in heart failure subjects (21) and have begun characterizing miR-mediated regulation via the SCN5A 3′-untranslated region (3′-UTR) (22)(23)(24). However, SCN5A encodes the voltage-gated Na + channel Na V 1.5 that is responsible for depolarization of the cardiac action potential and rapid intercellular conduction.…”

Section: Introductionmentioning

confidence: 99%

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A common variant alters SCN5A–miR-24 interaction and associates with heart failure mortality

Zhang¹,

Yoon²,

Morley³

et al. 2018

Journal of Clinical Investigation

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SCN5A encodes the voltage-gated Na+ channel NaV1.5 that is responsible for depolarization of the cardiac action potential and rapid intercellular conduction. Mutations disrupting the SCN5A coding sequence cause inherited arrhythmias and cardiomyopathy, and single-nucleotide polymorphisms (SNPs) linked to SCN5A splicing, localization, and function associate with heart failure-related sudden cardiac death. However, the clinical relevance of SNPs that modulate SCN5A expression levels remains understudied. We recently generated a transcriptome-wide map of microRNA (miR) binding sites in human heart, evaluated their overlap with common SNPs, and identified a synonymous SNP (rs1805126) adjacent to a miR-24 site within the SCN5A coding sequence. This SNP was previously shown to reproducibly associate with cardiac electrophysiological parameters, but was not considered to be causal. Here, we show that miR-24 potently suppresses SCN5A expression and that rs1805126 modulates this regulation. We found that the rs1805126 minor allele associates with decreased cardiac SCN5A expression and that heart failure subjects homozygous for the minor allele have decreased ejection fraction and increased mortality, but not increased ventricular tachyarrhythmias. In mice, we identified a potential basis for this in discovering that decreased Scn5a expression leads to accumulation of myocardial reactive oxygen species. Together, these data reiterate the importance of considering the mechanistic significance of synonymous SNPs as they relate to miRs and disease, and highlight a surprising link between SCN5A expression and nonarrhythmic death in heart failure.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

A common variant alters SCN5A–miR-24 interaction and associates with heart failure mortality

Zhang¹,

Yoon²,

Morley³

et al. 2018

Journal of Clinical Investigation

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“…Houria et al recently showed that miR-219 also regulated the expression of SCN5A , however, it increased the expression of both SCN5A mRNA and Na v 1.5 protein as well as I Na in HL1 cells derived from mouse atria [42]. MiRNAs normally down-regulates the expression of its downstream target genes either by inducing mRNA degradation or by inhibiting translation.…”

Section: Discussionmentioning

confidence: 99%

Post-transcriptional regulation of cardiac sodium channel gene SCN5A expression and function by miR-192-5p

Zhao

Huang

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The SCN5A gene encodes cardiac sodium channel Nav1.5 and causes lethal ventricular arrhythmias/sudden death and atrial fibrillation (AF) when mutated. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, and involved in the pathogenesis of many diseases. However, little is known about the regulation of SCN5A by miRNAs. Here we reveal a novel post-transcriptional regulatory mechanism for expression and function of SCN5A/Nav1.5 via miR-192-5p. Bioinformatic analysis revealed that the 3′-UTR of human and rhesus SCN5A, but not elephant, pig, rabbit, mouse, and rat SCN5A, contained a target binding site for miR-192-5p and dual luciferase reporter assays showed that the site was critical for down-regulation of human SCN5A. With Western blot assays and electrophysiological studies, we demonstrated that miR-192-5p significantly reduced expression of SCN5A and Nav1.5 as well as peak sodium current density INa generated by Nav1.5. Notably, in situ hybridization, immunohistochemistry and real-time qPCR analyses showed that miR-192-5p was up-regulated in tissue samples from AF patients, which was associated with down-regulation of SCN5A/Nav1.5. These results demonstrate an important post-transcriptional role of miR-192-5p in post-transcriptional regulation of Nav1.5, reveal a novel role of miR-192-5p in cardiac physiology and disease, and provide a new target for novel miRNA-based antiarrhythmic therapy for diseases with reduced INa.

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“…We here have identified the rs107822 which is an allele T/C alternated polymorphism located in flanking sequence-36 bp of pre-miR-219a. Since our previous findings demonstrated that miR-219a over expression severely increases Scn5a expression [11], so we hypothesized that rs107822 within pri-miR-219a would affect its structure or expression, leading to an impaired miR-219a expression (most likely decreasing) which in turn will lead to a decreased SCN5A expression. Recently, Song et al demonstrated that the miR-219a rs107822 GA and AA genotypes decreased the mature miR-219a expression compared with the miR-219a rs107822 GG genotypes in normal tissues which further supports our hypothesis [34] Although the functionality of this polymorphism has been studied in several pathological contexts including cancers and psychological disorders [35,36], to our knowledge, it's the first time that the rs107822 is identified in patients with cardiac diseases particularly BrS.…”

Section: Discussionmentioning

confidence: 99%

“…More recent studies suggested that miRNAs play important roles in cardiovascular diseases and particularly cardiac arrhythmias [9]. miRNAs are short noncoding RNA molecules that regulate gene expression by binding with the 3' UTR of their target genes, leading to the degradation or in some rare cases to the stabilization of their target's mRNA [10,11]. miRNAs are emerging as pivotal regulators of gene expression and protein translation involving processes such as cardiac remodeling, growth and arrhythmias [12,13,14,15].…”

Section: Introductionmentioning

confidence: 99%

Role of SCN5A coding and non-coding sequences in Brugada syndrome onset: What’s behind the scenes?

Daimi

Khelil

Neji

et al. 2017

Preprint

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Brugada syndrome (BrS) is a rare inherited cardiac arrhythmia associated with a high risk of sudden cardiac death (SCD) due to ventricular fibrillation (VF). BrS is characterized by coved-type ST-segment elevation in the right precordial leads (V1-V3) in the absence of structural heart disease. This pattern is spontaneous, or is unmasked by intravenous administration of Class I antiarrhythmic drugs. The SCN5A-encoded α -subunit of the NaV1.5 cardiac sodium channel has been linked to BrS, and mutations in SCN5A are identified in 15-30% of BrS cases. Genetic testing of BrS patients generally involves sequencing of protein-coding portions and flanking intronic regions of SCN5A, according to recent international guidelines. This excludes the regulatory untranslated regions (5'UTR and 3'UTR) from the routine genetic testing of BrS patients. We here screened the coding sequence, the flanking intronic regions as well as the 5' and 3'UTR regions of SCN5A gene and further five candidate genes (GPD1L, SCN1B, KCNE3, SCN4B, and MOG1) in a Tunisian family diagnosed with Brugada syndrome.A new Q1000K mutation was identified on the SCN5A gene along with two common polymorphisms (H558R and D1819). Furthermore, multiple genetic variants were identified on the SCN5A 3´UTR, one of which is predicted to create additional microRNA (miRNAs) binding site for miR-1270. Additionally, we identified the hsa-miR-219a rs107822. No relevant coding sequence variant was identified in the remaining studied candidate genes.Although Q1000K is localized in the conserved binding site of MOG1 which predicts a functional consequence, this new mutation along with the additional variants were differentially distributed among the family members without any clear genotype-phenotype concordance. This gives extra evidences about the complexity of the disease and suggests that the occurrence and prognosis of BrS is most likely controlled by a combination of multiple genetic factors and exposures, rather than a single polymorphism/mutation. Most SCN5A polymorphisms were localized in non-coding regions hypothesizing an impact on the miRNA-target complementarities. In this regard, over-

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Regulation of SCN5A by microRNAs: miR-219 modulates SCN5A transcript expression and the effects of flecainide intoxication in mice

Cited by 39 publications

References 27 publications

A common variant alters SCN5A–miR-24 interaction and associates with heart failure mortality

A common variant alters SCN5A–miR-24 interaction and associates with heart failure mortality

Post-transcriptional regulation of cardiac sodium channel gene SCN5A expression and function by miR-192-5p

Role of SCN5A coding and non-coding sequences in Brugada syndrome onset: What’s behind the scenes?

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