MADGene: retrieval and processing of gene identifier lists for the analysis of heterogeneous microarray datasets

Summary: MADGene is a software environment comprising a web-based database and a java application. This platform aims at unifying gene identifiers (ids) and performing gene set analysis. MADGene allows the user to perform inter-conversion of clone and gene ids over a large range of nomenclatures relative to 17 species. We propose a set of 23 functions to facilitate the analysis of gene sets and we give two microarray applications to show how MADGene can be used to conduct meta-analyses

Immune Response and Mitochondrial Metabolism Are Commonly Deregulated in DMD and Aging Skeletal Muscle

Duchenne Muscular Dystrophy (DMD) is a complex process involving multiple pathways downstream of the primary genetic insult leading to fatal muscle degeneration. Aging muscle is a multifactorial neuromuscular process characterized by impaired muscle regeneration leading to progressive atrophy. We hypothesized that these chronic atrophying situations may share specific myogenic adaptative responses at transcriptional level according to tissue remodeling. Muscle biopsies from four young DMD and four AGED subjects were referred to a group of seven muscle biopsies from young subjects without any neuromuscular disorder and explored through a dedicated expression microarray. We identified 528 differentially expressed genes (out of 2,745 analyzed), of which 328 could be validated by an exhaustive meta-analysis of public microarray datasets referring to DMD and Aging in skeletal muscle. Among the 328 validated co-expressed genes, 50% had the same expression profile in both groups and corresponded to immune/fibrosis responses and mitochondrial metabolism. Generalizing these observed meta-signatures with large compendia of public datasets reinforced our results as they could be also identified in other pathological processes and in diverse physiological conditions. Focusing on the common gene signatures in these two atrophying conditions, we observed enrichment in motifs for candidate transcription factors that may coordinate either the immune/fibrosis responses (ETS1, IRF1, NF1) or the mitochondrial metabolism (ESRRA). Deregulation in their expression could be responsible, at least in part, for the same transcriptome changes initiating the chronic muscle atrophy. This study suggests that distinct pathophysiological processes may share common gene responses and pathways related to specific transcription factors

Meta-analysis of muscle transcriptome data using the MADMuscle database reveals biologically relevant gene patterns

<p>Abstract</p> <p>Background</p> <p>DNA microarray technology has had a great impact on muscle research and microarray gene expression data has been widely used to identify gene signatures characteristic of the studied conditions. With the rapid accumulation of muscle microarray data, it is of great interest to understand how to compare and combine data across multiple studies. Meta-analysis of transcriptome data is a valuable method to achieve it. It enables to highlight conserved gene signatures between multiple independent studies. However, using it is made difficult by the diversity of the available data: different microarray platforms, different gene nomenclature, different species studied, etc.</p> <p>Description</p> <p>We have developed a system tool dedicated to muscle transcriptome data. This system comprises a collection of microarray data as well as a query tool. This latter allows the user to extract similar clusters of co-expressed genes from the database, using an input gene list. Common and relevant gene signatures can thus be searched more easily. The dedicated database consists in a large compendium of public data (more than 500 data sets) related to muscle (skeletal and heart). These studies included seven different animal species from invertebrates (<it>Drosophila melanogaster, Caenorhabditis elegans</it>) and vertebrates (<it>Homo sapiens, Mus musculus, Rattus norvegicus, Canis familiaris, Gallus gallus</it>). After a renormalization step, clusters of co-expressed genes were identified in each dataset. The lists of co-expressed genes were annotated using a unified re-annotation procedure. These gene lists were compared to find significant overlaps between studies.</p> <p>Conclusions</p> <p>Applied to this large compendium of data sets, meta-analyses demonstrated that conserved patterns between species could be identified. Focusing on a specific pathology (Duchenne Muscular Dystrophy) we validated results across independent studies and revealed robust biomarkers and new pathways of interest. The meta-analyses performed with MADMuscle show the usefulness of this approach. Our method can be applied to all public transcriptome data.</p

Insight into atrial fibrillation through analysis of the coding transcriptome in humans

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Cardiac aging and heart disease in humans

International audienceThe world population continues to grow older rapidly, mostly because of declining fertility and increasing longevity. Since age represents the largest risk factor for cardiovascular disease, the prevalence of these pathologies increases dramatically with increasing age. In order to improve patient care and prevention for age-related cardiac diseases, insight should be gained from the analysis of processes involved in and leading to cardiac aging. It is from this perspective that we provide here an overview of changes associated with age in the heart on four levels: functional, structural, cellular and molecular. We highlight those changes that are in common with the development of the two major age-associated cardiac pathologies: heart failure and atrial fibrillation. These commonly affected processes in aging and cardiac pathophysiology may provide an explanation for the age risk factor in cardiac disease

Portraits moléculaires des pathologies cardiaques

Les pathologies cardiaques représentent une cause majeure de morbidité et de mortalité. L'achèvement du séquençage du génome humain a permis le développement de nouvelles approches des maladies comme les études d'expression génique. Au moyen de puces à ADN, les travaux de cette thèse se sont centrés sur l'étude des variations transcriptomales survenant dans l'insuffisance cardiaque et la fibrillation auriculaire chez l'homme. Un profil d'expression génique permettant de prédire le niveau de sévérité clinique des patients en insuffisance cardiaque avancée a été identifié et pourrait servir de base au développement d un biomarqueur du pronostic. Dans la fibrillation auriculaire chronique, l'analyse des variations d expression génique a suggéré l existence d un phénotype tissulaire pro-thrombotique qui pourrait mieux expliquer le risque thromboembolique majeur de la maladie. Ces résultats ont globalement confirmé l'intérêt de l étude des variations transcriptomales dans les maladies cardiaques. La poursuite des travaux déjà engagés devrait non seulement permettre une meilleure compréhension des mécanismes moléculaires des pathologies mais également l'identification de biomarqueurs à but diagnostique, pronostique ou d'orientation thérapeutique.Cardiac diseases remains a major cause of mortality and morbidity. With the completion of the sequencing of the human genome, new techniques like gene expression profiling have been developped to study human diseases. Using DNA-microrrays, we analyzed transcriptomal alterations associated with heart failure and atrial fibrillation in humans. We identified a gene expression profile associated with clinical deterioration of advanced heart failure patients which may be used to better define patients prognosis. Gene expression alteration in chronic atrial fibrillation were suggestive of a hypercoagulable state, a result of potential importance to better understand the pathophysiology of thromboembolic events in atrial fibrillation. Taken together, these results show the great potential of gene expression profiling to study cardiac diseases. Further studies will improve our knowledge of pathological mecanisms occuring in these diseases and will probably provide us with new biomarkers for diagnosis, prognosis and therapy of cardiac diseases.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

A prokineticin-driven epigenetic switch regulates human epicardial cell stemness and fate

International audienceEpicardial adipose tissues (EAT) and vascular tissues may both belong to the mesoepithelial lineage that develops from epicardium-derived progenitor cells (EPDCs) in developing and injured hearts. Very little is known of the molecular mechanisms of EPDC contribution in EAT development and neovascularization in adult heart, which the topic remains a subject of intense therapeutic interest and scientific debate. Here we studied the epigenetic control of stemness and anti-adipogenic and pro-vasculogenic fate of hEPDCs, through investigating an angiogenic hormone, prokineticin-2 (PK2) signaling via its receptor PKR1. We found that hEPDCs spontaneously undergoes epithelial-to-mesenchymal transformation (EMT), and are not predestined for the vascular lineages. However, PK2 via a histone demethylase KDM6A inhibits EMT, and induces asymmetric division, leading to self-renewal and formation of vascular and epithelial/endothelial precursors with angiogenic potential capable of differentiating into vascular smooth muscle and endothelial cells. PK2 upregulates and activates KDM6A to inhibit repressive histone H3K27me3 marks on promoters of vascular genes (Flk-1 and SM22α) involved in vascular lineage commitment and maturation. In PK2-mediated anti-adipogenic signaling, KDM6A stabilizes and increases cytoplasmic β-catenin levels to repress PPARγ expression and activity. Our findings offer additional molecular targets to manipulate hEPDCs-involved tissue repair/regeneration in cardiometabolic and ischemic heart diseases. This article is protected by copyright. All rights reserved

Prokineticin receptor-1-dependent paracrine and autocrine pathways control cardiac tcf21(+) fibroblast progenitor cell transformation into adipocytes and vascular cells

International audienceCardiac fat tissue volume and vascular dysfunction are strongly associated, accounting for overall body mass. Despite its pathophysiological significance, the origin and autocrine/paracrine pathways that regulate cardiac fat tissue and vascular network formation are unclear. We hypothesize that adipocytes and vasculogenic cells in adult mice hearts may share a common cardiac cells that could transform into adipocytes or vascular lineages, depending on the paracrine and autocrine stimuli. In this study utilizing transgenic mice overexpressing prokineticin receptor (PKR1) in cardiomyocytes, and tcf21ERT-cre(TM)-derived cardiac fibroblast progenitor (CFP)-specific PKR1 knockout mice (PKR1 (tcf-/-)), as well as FACS-isolated CFPs, we showed that adipogenesis and vasculogenesis share a common CFPs originating from the tcf21(+) epithelial lineage. We found that prokineticin-2 is a cardiomyocyte secretome that controls CFP transformation into adipocytes and vasculogenic cells in vivo and in vitro. Upon HFD exposure, PKR1 (tcf-/-) mice displayed excessive fat deposition in the atrioventricular groove, perivascular area, and pericardium, which was accompanied by an impaired vascular network and cardiac dysfunction. This study contributes to the cardio-obesity field by demonstrating that PKR1 via autocrine/paracrine pathways controls CFP-vasculogenic- and CFP-adipocyte-transformation in adult heart. Our study may open up new possibilities for the treatment of metabolic cardiac diseases and atherosclerosis

Pressure Overload–Mediated Sustained PKR2 (Prokineticin-2 Receptor) Signaling in Cardiomyocytes Contributes to Cardiac Hypertrophy and Endotheliopathies

International audienceChronic cardiac pressure overload, caused by conditions, such as hypertension, induces pathological hypertrophic growth of myocardium and vascular rarefaction, with largely unknown mechanisms. Here, we described that expression of the PKR2 (prokineticin-2 receptor) is increased in the cardiomyocytes of mice following transaortic constriction pressure overload–mediated pathological hypertrophy. To identify PKR2-induced pathways, we performed microarray analysis on TG-PKR2 (transgenic mice overexpressing cardiomyocyte-restricted human PKR2) hearts and cytokine analyses in hPKR2 overexpressing H9c2-lines (PKR2-cardiomyocytes). An enrichment of activin pathway gene sets was found in both TG-PKR2 and transaortic constriction-operated hearts. Elevated levels of 2 cytokines activin A and its coreceptor, sENG (soluble Endoglin), were found in both PKR2-cardiomyocytes and in PKR2-cardiomyocytes conditioned medium. ELISA analyses of the cardiomyocytes derived from both TG-PKR2 and transaortic constriction hearts revealed high levels of these cardiokines that were repressed with antibodies blocking PKR2, indicating a PKR2-dependent event. The conditioned medium of PKR2-cardiomyocytes induced fenestration of endothelial cells and inhibited tube-like formations. These endotheliopathies were blocked by either depleting activin A or sENG from conditioned medium or by using 2 pharmacological inhibitors, follistatin, and TRC105. In addition, similar endotheliopathies were produced by exogenous administration of activin A and ENG. Prolonged exposure to prokineticin-2 in PKR2-cardiomyocytes increased cell volume by the PKR2/Gα 12/13 /ERK5-pathway. Activation of the PKR2/Gα 12/13 /matrix metalloprotease-pathway promoted both activin A and sENG release. This study reveals that pressure overload–mediated PKR2 signaling in cardiomyocytes contributes to cardiac hypertrophy through autocrine signaling, and vascular rarefaction via cardiac cytokine-mediated cardiomyocyte–endothelial cell communications. Our results may contribute to the development of potential therapeutic targets for heart failure

The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis

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