Atrial fibrillation is associated with hypermethylation in human left atrium, and treatment with decitabine reduces atrial tachyarrhythmias in spontaneously hypertensive rats

Puertas, Rosa Doñate; Meugnier, Emmanuelle; Romestaing, Caroline; Rey, Colette; Morel, E.; Lachuer, Joël; Gadot, Nicolas; Scridon, Alina; Julien, Claude; Tronc, François; Chapuis, Bruno; Valla, C.; Janin, Alexandre; Pirola, Luciano; Méjat, Alexandre; Rome, Sophie; Chevalier, Philippe

doi:10.1016/j.trsl.2017.03.004

Cited by 28 publications

(23 citation statements)

References 36 publications

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“…Proteins involved in the desmosome structure include that encoded by DSG2 and DSP . DSG2 is more expressed in LA of patients with AF than control subjects as previously described [ 24 ]. Transcriptional network of cardiac rhythm driven by TBX5 and modulated by PITX2 regulates Scn5a , Gja1 , Ryr2 , Dsp , and Atp2a2 genes [ 43 ].…”

Section: Discussionmentioning

confidence: 92%

“…Genomic DNA samples underwent NGS using a custom AmpliSeq design (Life Technologies, Carlsbad, CA, USA) created using Ion AmpliSeq designer software. In the first step, the criteria for gene selection were based on the previously reported transcriptome of atrial tissue in patients with AF [ 24 ]. We found that 1,627 genes had altered basal expression levels in the LA tissue of patients with AF compared with the control group.…”

Section: Methodsmentioning

confidence: 99%

“… Supplementary Figure 1 : schematic overview of our approach in atrial fibrillation (AF) patients. According to our previous transcriptomic data on left atrium (LA) in AF patients that highlighted the structural genes [ 24 ], a next-generation sequencing (NGS) approach has been applied to a cohort of 94 AF patients. Eleven potentially pathogenic variants were identified in AF patients, mainly in those with atrial dilatation, through a custom-made panel of 55 genes potentially involved in atrial myopathy.…”

Section: Supplementary Materialsmentioning

confidence: 99%

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Atrial Structural Remodeling Gene Variants in Patients with Atrial Fibrillation

Puertas

Millat

Ernens

et al. 2018

BioMed Research International

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Atrial fibrillation (AF) is a common arrhythmia for which the genetic studies mainly focused on the genes involved in electrical remodeling, rather than left atrial muscle remodeling. To identify rare variants involved in atrial myopathy using mutational screening, a high-throughput next-generation sequencing (NGS) workflow was developed based on a custom AmpliSeq™ panel of 55 genes potentially involved in atrial myopathy. This workflow was applied to a cohort of 94 patients with AF, 76 with atrial dilatation and 18 without. Bioinformatic analyses used NextGENe® software and in silico tools for variant interpretation. The AmpliSeq custom-made panel efficiently explored 96.58% of the targeted sequences. Based on in silico analysis, 11 potentially pathogenic missense variants were identified that were not previously associated with AF. These variants were located in genes involved in atrial tissue structural remodeling. Three patients were also carriers of potential variants in prevalent arrhythmia-causing genes, usually associated with AF. Most of the variants were found in patients with atrial dilatation (n=9, 82%). This NGS approach was a sensitive and specific method that identified 11 potentially pathogenic variants, which are likely to play roles in the predisposition to left atrial myopathy. Functional studies are needed to confirm their pathogenicity.

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Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Supplementary Materialsmentioning

confidence: 99%

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Atrial Structural Remodeling Gene Variants in Patients with Atrial Fibrillation

Puertas

Millat

Ernens

et al. 2018

BioMed Research International

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“…In the context of AF, a group of miRNAs have been identified for being able to be involved in AF as regulators of ion-channel proteins [ 36 ] or to be related to AF development, based on their altered basal expression in atria of patient suffering from AF [ 37 , 38 ]. Recently, we have performed a transcriptomic analysis on human LA from patients with valvular heart disease (VHD) associated with or without AF in order to identify the transcriptional signature specifically related to the AF condition and demonstrated that promoter hypermethylation was associated to some of these transcriptional alterations [ 39 ]. In order to determine whether miRNA dysregulation could also be associated with heart remodeling associated with AF development ( i .…”

Section: Introductionmentioning

confidence: 99%

“…TNRC6 proteins), further suggesting that alteration of miRNAs in LA would in fact perturbate the whole miRNome. Further bioinformatic analyses suggested that these altered miRNAs might explain part of the altered transcriptional signature previously identified as associated with the pathology [ 39 ], as altered miRNA were predicted to target half of the altered mRNA in LA of AF patients.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the microRNA signature in left atrium from patients with valvular heart disease reveals their implications in atrial fibrillation

et al. 2018

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BackgroundAmong the potential factors which may contribute to the development and perpetuation of atrial fibrillation, dysregulation of miRNAs has been suggested. Thus in this study, we have quantified the basal expressions of 662 mature human miRNAs in left atrium (LA) from patients undergoing cardiac surgery for valve repair, suffering or not from atrial fibrillation (AF) by using TaqMan® Low Density arrays (v2.0).ResultsAmong the 299 miRNAs expressed in all patients, 42 miRNAs had altered basal expressions in patients with AF. Binding-site predictions with Targetscan (conserved sites among species) indicated that the up- and down-regulated miRNAs controlled respectively 3,310 and 5,868 genes. To identify the most relevant cellular functions under the control of the altered miRNAs, we focused on the 100 most targeted genes of each list and identified 5 functional protein-protein networks among these genes. Up-regulated networks were involved in synchronisation of circadian rythmicity and in the control of the AKT/PKC signaling pathway (i.e., proliferation/adhesion). Down-regulated networks were the IGF-1 pathway and TGF-beta signaling pathway and a network involved in RNA-mediated gene silencing, suggesting for the first time that alteration of miRNAs in AF would also perturbate the whole miRNA machinery. Then we crossed the list of miRNA predicted genes, and the list of mRNAs altered in similar patients suffering from AF and we found that respectively 44.5% and 55% of the up- and down-regulated mRNA are predicted to be conserved targets of the altered miRNAs (at least one binding site in 3’-UTR). As they were involved in the same biological processes mentioned above, these data demonstrated that a great part of the transcriptional defects previously published in LA from AF patients are likely due to defects at the post-transcriptional level and involved the miRNAs.ConclusionsOur stringent analysis permitted us to identify highly targeted protein-protein networks under the control of miRNAs in LA and, among them, to highlight those specifically affected in AF patients with altered miRNA signature. Further studies are now required to determine whether alterations of miRNA levels in AF pathology are causal or represent an adaptation to prevent cardiac electrical and structural remodeling.

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Antiarrhythmic Properties of Non-Antiarrhythmic Drugs in Atrial Fibrillation: Upstream Therapy

Scridon

Martínez‐Rubio

2020

Antiarrhythmic Drugs

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Atrial fibrillation is associated with hypermethylation in human left atrium, and treatment with decitabine reduces atrial tachyarrhythmias in spontaneously hypertensive rats

Cited by 28 publications

References 36 publications

Atrial Structural Remodeling Gene Variants in Patients with Atrial Fibrillation

Atrial Structural Remodeling Gene Variants in Patients with Atrial Fibrillation

Analysis of the microRNA signature in left atrium from patients with valvular heart disease reveals their implications in atrial fibrillation

Antiarrhythmic Properties of Non-Antiarrhythmic Drugs in Atrial Fibrillation: Upstream Therapy

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