Whole-Genome Cardiac DNA Methylation Fingerprint and Gene Expression Analysis Provide New Insights in the Pathogenesis of Chronic Chagas Disease Cardiomyopathy

Laugier, Laurie; Frade, Amanda Farage; Ferreira, Frederico Moraes; Baron, Monique; Teixeira, Priscila Camillo; Cabantous, Stéphanie; Ferreira, Ludmila Rodrigues Pinto; Louis, Laurence; Rigaud, Vagner Oliveira Carvalho; Gaiotto, Fábio Antônio; Bacal, Fernando; Pomerantzeff, Pablo Maria Alberto; Bocchi, Edimar Alcides; Kalil, Jorge; Santos, Ronaldo Honorato Barros; Cunha-Neto, Edécio; Chevillard, Christophe

doi:10.1093/cid/cix506

Cited by 58 publications

(50 citation statements)

References 37 publications

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“…The confirmation rate was 86%, and only for 6 genes (ABRA, CDC42, ESRRA, GPD1, NFATC2, TGFBR2), the expression patterns were not confirmed. The gene specific qRT-PCR results, including fold change and p values, were previously described ([ 39 ], S2 Table ).…”

Section: Resultsmentioning

confidence: 99%

miRNAs may play a major role in the control of gene expression in key pathobiological processes in Chagas disease cardiomyopathy

Laugier

Ferreira

et al. 2020

PLoS Negl Trop Dis

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Chronic Chagas disease cardiomyopathy (CCC), an especially aggressive inflammatory dilated cardiomyopathy caused by lifelong infection with the protozoan Trypanosoma cruzi, is a major cause of cardiomyopathy in Latin America. Although chronic myocarditis may play a major pathogenetic role, little is known about the molecular mechanisms responsible for its severity. The aim of this study is to study the genes and microRNAs expression in tissues and their connections in regards to the pathobiological processes. To do so, we integrated for the first time global microRNA and mRNA expression profiling from myocardial tissue of CCC patients employing pathways and network analyses. We observed an enrichment in biological processes and pathways associated with the immune response and metabolism. IFNγ, TNF and NFkB were the top upstream regulators. The intersections between differentially expressed microRNAs and differentially expressed target mRNAs showed an enrichment in biological processes such as Inflammation, inflammation, Th1/IFN-γ-inducible genes, fibrosis, hypertrophy, and mitochondrial/oxidative stress/antioxidant response. MicroRNAs also played a role in the regulation of gene expression involved in the key cardiomyopathy-related processes fibrosis, hypertrophy, myocarditis and arrhythmia. Significantly, a discrete number of differentially expressed microRNAs targeted a high number of differentially expressed mRNAs (>20) in multiple processes. Our results suggest that miRNAs orchestrate expression of multiple genes in the major pathophysiological processes in CCC heart tissue. This may have a bearing on pathogenesis, biomarkers and therapy.

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Section: Resultsmentioning

confidence: 99%

miRNAs may play a major role in the control of gene expression in key pathobiological processes in Chagas disease cardiomyopathy

Laugier

Ferreira

et al. 2020

PLoS Negl Trop Dis

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“…More recently, whole blood transcriptional profiling has been used to study human host responses to protozoan pathogens such as malaria [20, 21] and Chagas disease caused by Trypanosoma cruzi [22, 23]. Expression profiling has also been applied in the context of animal models [24–26] and in human studies [15, 27–29] of the leishmaniases.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional blood signatures for active and amphotericin B treated visceral leishmaniasis in India

et al. 2019

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Amphotericin B provides improved therapy for visceral leishmaniasis (VL) caused by Leishmania donovani , with single dose liposomal-encapsulated Ambisome providing the best cure rates. The VL elimination program aims to reduce the incidence rate in the Indian subcontinent to <1/10,000 population/year. Ability to predict which asymptomatic individuals (e.g. anti-leishmanial IgG and/or Leishmania-specific modified Quantiferon positive) will progress to clinical VL would help in monitoring disease outbreaks. Here we examined whole blood transcriptional profiles associated with asymptomatic infection, active disease, and in treated cases. Two independent microarray experiments were performed, with analysis focussed primarily on differentially expressed genes (DEGs) concordant across both experiments. No DEGs were identified for IgG or Quantiferon positive asymptomatic groups compared to negative healthy endemic controls. We therefore concentrated on comparing concordant DEGs from active cases with all healthy controls, and in examining differences in the transcriptome following different regimens of drug treatment. In these comparisons 6 major themes emerged: (i) expression of genes and enrichment of gene sets associated with erythrocyte function in active cases; (ii) strong evidence for enrichment of gene sets involved in cell cycle in comparing active cases with healthy controls; (iii) identification of IFNG encoding interferon-γ as the major hub gene in concordant gene expression patterns across experiments comparing active cases with healthy controls or with treated cases; (iv) enrichment for interleukin signalling (IL-1/3/4/6/7/8) and a prominent role for CXCL10/9/11 and chemokine signalling pathways in comparing active cases with treated cases; (v) the novel identification of Aryl Hydrocarbon Receptor signalling as a significant canonical pathway when comparing active cases with healthy controls or with treated cases; and (vi) global expression profiling support for more effective cure at day 30 post-treatment with a single dose of liposomal encapsulated amphotericin B compared to multi-dose non-liposomal amphotericin B treatment over 30 days. (296 words; 300 words allowed).

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“…SMOC2 could be a potential significance factor that altered remodeling and inflammation for further study in the mechanism of HF. Laugier et al (2017) found that SMOC2 , involved in matrix remodeling, is potentially associated with the increased T-helper 1 cytokine-mediated inflammatory damage in heart, using genome-wide cardiac DNA methylation on global gene expression in myocardial samples in chronic Chagas disease cardiomyopathy, which is an inflammatory cardiomyopathy presenting with heart failure and arrhythmia.…”

Section: Resultsmentioning

confidence: 99%

Multiple Feature Selection Strategies Identified Novel Cardiac Gene Expression Signature for Heart Failure

Lin²,

2020

Front. Physiol.

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Heart failure (HF) is a serious condition in which the support of blood pumped by the heart is insufficient to meet the demands of body at a normal cardiac filling pressure. Approximately 26 million patients worldwide are suffering from heart failure and about 17–45% of patients with heart failure die within 1-year, and the majority die within 5-years admitted to a hospital. The molecular mechanisms underlying the progression of heart failure have been poorly studied. We compared the gene expression profiles between patients with heart failure ( n = 177) and without heart failure ( n = 136) using multiple feature selection strategies and identified 38 HF signature genes. The support vector machine (SVM) classifier based on these 38 genes evaluated with leave-one-out cross validation (LOOCV) achieved great performance with sensitivity of 0.983 and specificity of 0.963. The network analysis suggested that the hub gene SMOC2 may play important roles in HF. Other genes, such as FCN3 , HMGN2 , and SERPINA3 , also showed great promises. Our results can facilitate the early detection of heart failure and can reveal its molecular mechanisms.

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Whole-Genome Cardiac DNA Methylation Fingerprint and Gene Expression Analysis Provide New Insights in the Pathogenesis of Chronic Chagas Disease Cardiomyopathy

Abstract: SummaryDNA methylation analysis on global gene expression in myocardial samples from patients with end-stage chronic Chagas cardiomyopathy leads to the identification of novel potential disease pathways and therapeutic targets linked to electrical conduction or immune response modulation.

Cited by 58 publications

References 37 publications

miRNAs may play a major role in the control of gene expression in key pathobiological processes in Chagas disease cardiomyopathy

miRNAs may play a major role in the control of gene expression in key pathobiological processes in Chagas disease cardiomyopathy

Transcriptional blood signatures for active and amphotericin B treated visceral leishmaniasis in India

Multiple Feature Selection Strategies Identified Novel Cardiac Gene Expression Signature for Heart Failure

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