Investigating gene-microRNA networks in atrial fibrillation patients with mitral valve regurgitation

Santos, Joana Larupa; Rodríguez, Ismael; Olesen, Morten; Bentzen, Bo Hjorth; Schmitt, Nicole

doi:10.1371/journal.pone.0232719

Cited by 12 publications

(8 citation statements)

References 75 publications

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“…We performed a similar analysis of the systematic mutagenesis of other atrium- and ventricle-selective enhancers (Figure S10E–S10G). For example, an atrial-selective enhancer (chr6:30 545 609–30 546 008) linked by H3K27ac HiChIP to Mir335, an atrial fibrillation–associated microRNA, 36 required the T-box motif in bins 43 to 44 and 51 to 52 (Figure S10F) for atrial selectivity (V/A-Mut track), and deletion of bin 50 significantly increased enhancer activity in ventricle (Mut/WT A and V tracks). Thus, systematic mutagenesis of this enhancer identified T-box binding sites essential to its atrial-selective activity, through enhancer activation in aCMs and repression in vCMs.…”

Section: Resultsmentioning

confidence: 99%

In Vivo Dissection of Chamber-Selective Enhancers Reveals Estrogen-Related Receptor as a Regulator of Ventricular Cardiomyocyte Identity

et al. 2023

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BACKGROUND: Cardiac chamber-selective transcriptional programs underpin the structural and functional differences between atrial and ventricular cardiomyocytes (aCMs and vCMs). The mechanisms responsible for these chamber-selective transcriptional programs remain largely undefined. METHODS: We nominated candidate chamber-selective enhancers (CSEs) by determining the genome-wide occupancy of 7 key cardiac transcription factors (GATA4, MEF2A, MEF2C, NKX2-5, SRF, TBX5, TEAD1) and transcriptional coactivator P300 in atria and ventricles. Candidate enhancers were tested using an adeno-associated virus–mediated massively parallel reporter assay. Chromatin features of CSEs were evaluated by performing assay of transposase accessible chromatin sequencing and acetylation of histone H3 at lysine 27-highly integrative chromatin immunoprecipitation on aCMs and vCMs. CSE sequence requirements were determined by systematic tiling mutagenesis of 29 CSEs at 5 bp resolution. Estrogen-related receptor (ERR) function in cardiomyocytes was evaluated by Cre-loxP–mediated inactivation of ERRα and ERRγ in cardiomyocytes. RESULTS: We identified 152 832 and 54 824 regions reproducibly occupied by at least 1 transcription factor or P300, in atria or ventricles, respectively. Enhancer activities of 2639 regions bound by transcription factors or P300 were tested in aCMs and vCMs by adeno-associated virus–mediated massively parallel reporter assay. This identified 1092 active enhancers in aCMs or vCMs. Several overlapped loci associated with cardiovascular disease through genome-wide association studies, and 229 exhibited chamber-selective activity in aCMs or vCMs. Many CSEs exhibited differential chromatin accessibility between aCMs and vCMs, and CSEs were enriched for aCM- or vCM-selective acetylation of histone H3 at lysine 27–anchored loops. Tiling mutagenesis of 29 CSEs identified the binding motif of ERRα/γ as important for ventricular enhancer activity. The requirement of ERRα/γ to activate ventricular CSEs and promote vCM identity was confirmed by loss of the vCM gene profile in ERRα/γ knockout vCMs. CONCLUSIONS: We identified 229 CSEs that could be useful research tools or direct therapeutic gene expression. We showed that chamber-selective multi–transcription factor, P300 occupancy, open chromatin, and chromatin looping are predictive features of CSEs. We found that ERRα/γ are essential for maintenance of ventricular identity. Finally, our gene expression, epigenetic, 3-dimensional genome, and enhancer activity atlas provide key resources for future studies of chamber-selective gene regulation.

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Section: Resultsmentioning

confidence: 99%

In Vivo Dissection of Chamber-Selective Enhancers Reveals Estrogen-Related Receptor as a Regulator of Ventricular Cardiomyocyte Identity

et al. 2023

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“…Santos et al [ 39 ] analyzed the miRNA profile of heart biopsies from atrial fibrillation (AF) patients, reporting that miR-130b-3p, miR-208a-3p, and miR-338-5p were differentially expressed in AF tissue samples.…”

Section: Resultsmentioning

confidence: 99%

miRNA Dysregulation in Cardiovascular Diseases: Current Opinion and Future Perspectives

Sessa

Salerno

Esposito

et al. 2023

IJMS

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MicroRNAs (miRNAs), small noncoding RNAs, are post-transcriptional gene regulators that can promote the degradation or decay of coding mRNAs, regulating protein synthesis. Many experimental studies have contributed to clarifying the functions of several miRNAs involved in regulatory processes at the cardiac level, playing a pivotal role in cardiovascular disease (CVD). This review aims to provide an up-to-date overview, with a focus on the past 5 years, of experimental studies on human samples to present a clear background of the latest advances to summarize the current knowledge and future perspectives. SCOPUS and Web of Science were searched using the following keywords: (miRNA or microRNA) AND (cardiovascular diseases); AND (myocardial infarction); AND (heart damage); AND (heart failure), including studies published from 1 January 2018 to 31 December 2022. After an accurate evaluation, 59 articles were included in the present systematic review. While it is clear that miRNAs are powerful gene regulators, all the underlying mechanisms remain unclear. The need for up-to-date data always justifies the enormous amount of scientific work to increasingly highlight their pathways. Given the importance of CVDs, miRNAs could be important both as diagnostic and therapeutic (theranostic) tools. In this context, the discovery of “TheranoMIRNAs” could be decisive in the near future. The definition of well-setout studies is necessary to provide further evidence in this challenging field.

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“…To emphasize the ability of our canine AF models to potentially capture early transcriptomic changes which would be missed by profiling the atria of human AF patients who have developed the disease over years, we compared the DE genes identified in AF dogs with results from two recent human atrial transcriptomic profiling experiments 25–26 . We found a single miRNA, MIRLET7F2 , that is DE in both dog and human AF samples ( Table S5 ).…”

Section: Resultsmentioning

confidence: 99%

“…We compared differentially expressed (DE) genes in our canine AF models with annotated human orthologues that are DE in human AF atrial tissue 25–26 .…”

Section: Resultsmentioning

confidence: 99%

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Transcriptomic profiling of canine atrial fibrillation models after one week of sustained arrhythmia

Leblanc

Liesinger

et al. 2021

Preprint

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Atrial fibrillation (AF), the most common arrhythmia with an overall prevalence of 0.51%, is associated with increased morbidity and mortality, as well as important healthcare costs. AF develops over many years and is often associated with substantial changes in the structural and electrophysiological properties of the atria. Because AF may lack subclinical symptoms at onset, it has been difficult to study the molecular and cellular events associated with earlier stages of this pathology in humans. Here, we characterized comprehensively the transcriptomic changes that occur in the atria of two robust canine AF models, electrically maintained AF without and with a controlled ventricular rate achieved by radiofrequency-ablation of the atrioventricular node (ventricular pacing), after one week of maintenance. Our RNA-sequencing experiments identified thousands of genes that are differentially expressed, including a majority that have never before been implicated in AF. Gene set enrichment analyses identified known (e.g. extracellular matrix structure organization) but also many novel pathways (e.g. muscle structure development, striated muscle cell differentiation) that may play a role in tissue remodeling and/or cellular trans-differentiation. Of interest, we found dysregulation of a cluster of non-coding ribonucleic acids (RNAs), including many microRNAs but also the MEG3 long non-coding RNA orthologue, located in the syntenic region of the imprinted human DLK1-DIO3 locus. Our results capture molecular events that occur at an early stage of disease development using well-characterized animal models, and may therefore inform future studies that aim to further dissect the causes of AF and factors involved in its progression in humans.

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Investigating gene-microRNA networks in atrial fibrillation patients with mitral valve regurgitation

Cited by 12 publications

References 75 publications

In Vivo Dissection of Chamber-Selective Enhancers Reveals Estrogen-Related Receptor as a Regulator of Ventricular Cardiomyocyte Identity

In Vivo Dissection of Chamber-Selective Enhancers Reveals Estrogen-Related Receptor as a Regulator of Ventricular Cardiomyocyte Identity

miRNA Dysregulation in Cardiovascular Diseases: Current Opinion and Future Perspectives

Transcriptomic profiling of canine atrial fibrillation models after one week of sustained arrhythmia

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