Modulation of ADAR mRNA expression in patients with congenital heart defects

Altaf, Faiza; Vesely, Cornelia; Sheikh, Abdul Malik; Munir, Rubab; Shah, S. P.; Tariq, Aamira

doi:10.1371/journal.pone.0200968

Cited by 27 publications

(35 citation statements)

References 53 publications

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“…Notably, dsRNA stem-loop structures formed by inverted repeated Alu (IRAlus) elements have been associated with the formation of circular RNA (circRNA) [34,48,83]. Both ADAR enzymes are expressed in the human heart [3]. We observed an increase in ADAR1 and a reduction in ADAR2 in the failing heart.…”

Section: Discussionmentioning

confidence: 78%

Reduction of A-to-I RNA editing in the failing human heart regulates formation of circular RNAs

et al. 2022

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Alterations of RNA editing that affect the secondary structure of RNAs can cause human diseases. We therefore studied RNA editing in failing human hearts. Transcriptome sequencing showed that adenosine-to-inosine (A-to-I) RNA editing was responsible for 80% of the editing events in the myocardium. Failing human hearts were characterized by reduced RNA editing. This was primarily attributable to Alu elements in introns of protein-coding genes. In the failing left ventricle, 166 circRNAs were upregulated and 7 circRNAs were downregulated compared to non-failing controls. Most of the upregulated circRNAs were associated with reduced RNA editing in the host gene. ADAR2, which binds to RNA regions that are edited from A-to-I, was decreased in failing human hearts. In vitro, reduction of ADAR2 increased circRNA levels suggesting a causal effect of reduced ADAR2 levels on increased circRNAs in the failing human heart. To gain mechanistic insight, one of the identified upregulated circRNAs with a high reduction of editing in heart failure, AKAP13, was further characterized. ADAR2 reduced the formation of double-stranded structures in AKAP13 pre-mRNA, thereby reducing the stability of Alu elements and the circularization of the resulting circRNA. Overexpression of circAKAP13 impaired the sarcomere regularity of human induced pluripotent stem cell-derived cardiomyocytes. These data show that ADAR2 mediates A-to-I RNA editing in the human heart. A-to-I RNA editing represses the formation of dsRNA structures of Alu elements favoring canonical linear mRNA splicing and inhibiting the formation of circRNAs. The findings are relevant to diseases with reduced RNA editing and increased circRNA levels and provide insights into the human-specific regulation of circRNA formation.

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Section: Discussionmentioning

confidence: 78%

Reduction of A-to-I RNA editing in the failing human heart regulates formation of circular RNAs

et al. 2022

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“…Although the study of RNA modifications, epitranscriptomics remains in its infancy, methodological breakthroughs of the last decade have enabled identification of these modifications with such accuracy that their large-scale screening is rational [ 117 , 118 , 119 , 120 , 121 , 143 ]. Encouragingly, research findings suggest both m 6 A and A-to-I to act as contributors or even potential initiators and drivers for several cardiovascular physiological and pathological processes including cardiogenesis, angiogenesis, hypertension, hypertrophy, atherosclerosis, ischemia, ischemia-reperfusion, fibrosis, HF, congenital heart disease, stroke, aneurysms, as well as cardiac repair and regeneration [ 25 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 51 , 52 , 53 , 54 , 55 , 56 ]. Remarkably, the first indication for coronary atherosclerosis to be reflected in the m 6 A content of mRNAs and long non-coding RNAs of peripheral mononuclear cells with suggested involvement in its pathophysiology has just recently been reported [ 151 ].…”

Section: Discussionmentioning

confidence: 99%

“…Like m 6 A, A-to-I editing contributes to RNA stability and innate immunity, but also regulates RNA splicing as well as miRNA biogenesis and function [ 22 , 49 , 50 ]. Changes in the RNA A-to-I modification landscape have been associated with pathologies including cancer, neurological impairment [ 49 ], and cardiovascular disease [ 25 , 51 , 52 , 53 , 54 , 55 , 56 ].…”

Section: Introductionmentioning

confidence: 99%

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

Sikorski

Karjalainen

Blokhina

et al. 2021

IJMS

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Epitranscriptomic modifications in RNA can dramatically alter the way our genetic code is deciphered. Cells utilize these modifications not only to maintain physiological processes, but also to respond to extracellular cues and various stressors. Most often, adenosine residues in RNA are targeted, and result in modifications including methylation and deamination. Such modified residues as N-6-methyl-adenosine (m6A) and inosine, respectively, have been associated with cardiovascular diseases, and contribute to disease pathologies. The Ischemic Heart Disease Epitranscriptomics and Biomarkers (IHD-EPITRAN) study aims to provide a more comprehensive understanding to their nature and role in cardiovascular pathology. The study hypothesis is that pathological features of IHD are mirrored in the blood epitranscriptome. The IHD-EPITRAN study focuses on m6A and A-to-I modifications of RNA. Patients are recruited from four cohorts: (I) patients with IHD and myocardial infarction undergoing urgent revascularization; (II) patients with stable IHD undergoing coronary artery bypass grafting; (III) controls without coronary obstructions undergoing valve replacement due to aortic stenosis and (IV) controls with healthy coronaries verified by computed tomography. The abundance and distribution of m6A and A-to-I modifications in blood RNA are charted by quantitative and qualitative methods. Selected other modified nucleosides as well as IHD candidate protein and metabolic biomarkers are measured for reference. The results of the IHD-EPITRAN study can be expected to enable identification of epitranscriptomic IHD biomarker candidates and potential drug targets.

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“…Even after FDR correction, we still have found 38 and 8 significantly different genes in hCM and hCF, respectively. We have not found any particular relation between them; however, some of them might play a role in processes such as protein synthesis regulation in cardiomyocytes (PABPC1 [ 39 ]), cardiac differentiation and development (FURIN [ 40 ]; ADAR [ 41 ]), or cellular response to viral infection (TMED2 [ 42 ]). Complex response of both cell lines to the acute MCD serum treatment, especially in the context of disturbed canonical pathways and cardiac disease-related genes, suggest our model as efficient way to investigate the effects of systemic inflammation on cardiac cells in the course of MCD.…”

Section: Discussionmentioning

confidence: 99%

Primary Human Cardiomyocytes and Cardiofibroblasts Treated with Sera from Myocarditis Patients Exhibit an Increased Iron Demand and Complex Changes in the Gene Expression

Kobak

Franczuk

Schubert

et al. 2021

Cells

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Cardiac fibroblasts and cardiomyocytes are the main cells involved in the pathophysiology of myocarditis (MCD). These cells are especially sensitive to changes in iron homeostasis, which is extremely important for the optimal maintenance of crucial cellular processes. However, the exact role of iron status in the pathophysiology of MCD remains unknown. We cultured primary human cardiomyocytes (hCM) and cardiofibroblasts (hCF) with sera from acute MCD patients and healthy controls to mimic the effects of systemic inflammation on these cells. Next, we performed an initial small-scale (n = 3 per group) RNA sequencing experiment to investigate the global cellular response to the exposure on sera. In both cell lines, transcriptomic data analysis revealed many alterations in gene expression, which are related to disturbed canonical pathways and the progression of cardiac diseases. Moreover, hCM exhibited changes in the iron homeostasis pathway. To further investigate these alterations in sera-treated cells, we performed a larger-scale (n = 10 for controls, n = 18 for MCD) follow-up study and evaluated the expression of genes involved in iron metabolism. In both cell lines, we demonstrated an increased expression of transferrin receptor 1 (TFR1) and ferritin in MCD serum-treated cells as compared to controls, suggesting increased iron demand. Furthermore, we related TFR1 expression with the clinical profile of patients and showed that greater iron demand in sera-treated cells was associated with higher inflammation score (interleukin 6 (IL-6), C-reactive protein (CRP)) and advanced neurohormonal activation (NT-proBNP) in patients. Collectively, our data suggest that the malfunctioning of cardiomyocytes and cardiofibroblasts in the course of MCD might be related to alterations in the iron homeostasis.

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Modulation of ADAR mRNA expression in patients with congenital heart defects

Cited by 27 publications

References 53 publications

Reduction of A-to-I RNA editing in the failing human heart regulates formation of circular RNAs

Reduction of A-to-I RNA editing in the failing human heart regulates formation of circular RNAs

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

Primary Human Cardiomyocytes and Cardiofibroblasts Treated with Sera from Myocarditis Patients Exhibit an Increased Iron Demand and Complex Changes in the Gene Expression

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