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Unravelling the etiology of dilated cardiomyopathy through differential miRNA-mRNA interactome

ABSTRACT: Dilated cardiomyopathy (DCM) entails a broad group of diseases, acquired or genetic, that share a similar phenotype. The understanding of gene-specific pathogenetic mechanisms and the determination of the functional effects of each variant may tailor different therapeutic strategies. MicroRNAs (miRNAs) are short sequences of non-coding RNA that play an important role in the development of several cardiovascular diseases, including DCM. Here, we applied mRNA and small RNA sequencing to identify the gene and miRNA signature from myocardial biopsies from four patients with DCM caused by volume overload (VCM) and four with ischemic DCM (ICM). Analysis showed five miRNAs and 112 mRNAs dysregulated in VCM vs ICM. Differentially expressed genes were positively enriched for extracellular matrix (ECM), mitochondria respiration-related, cardiac muscle contraction and fatty acid pathways in VCM vs ICM, and negatively enriched for immune response-related pathways, JAK-STAT and NF-kappa B signaling pathways in VCM vs ICM. miRNA-mRNA interaction analysis revealed four negatively correlated miRNA-target transcript pairs, miR-218-5p-DDX6, miR-218-5p-TT39C, miR-218-5p-SEMA4A and miR-494-3p-SGMS2. qRT-PCR validation showed a strong correlation between RNA-seq and qRT-PCR for these genes and miRNAs. These findings suggest that transcriptome signatures may distinguish distinct etiologies of DCM shedding light on underlying biological differences between VCM and ICM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243406 | GEO | 2024/05/29

REPOSITORIES: GEO

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Project description:Background: Newer 3D culturing approaches are a promising way to better mimic the in vivo tumor microenvironment and to study the interactions between the heterogeneous cell populations of glioblastoma multiforme. Like many other tumors, glioblastoma uses extracellular vesicles as an intercellular communication system to prepare surrounding tissue for invasive tumor growth. However, little is known about the effects of 3D culture on extracellular vesicles. The aim of this study was to comprehensively characterise extracellular vesicles in 3D organoid models and compare them to conventional 2D cell culture systems.Methods: Primary glioblastoma cells were cultured as 2D and 3D organoid models. Extracellular vesicles were obtained by precipitation and immunoaffinity, with the latter allowing targeted isolation of the CD9/CD63/CD81 vesicle subpopulation. Comprehensive vesicle characterisation was performed and miRNA expression profiles were generated by smallRNA-sequencing. In silico analysis of differentially regulated miRNAs was performed to identify mRNA targets and corresponding signaling pathways. The tumor cell media and extracellular vesicle proteome were analysed by high-resolution mass spectrometry.Results: We observed an increased concentration of extracellular vesicles in 3D organoid cultures. Differential gene expression analysis further revealed the regulation of twelve miRNAs in 3D tumor organoid cultures (with nine miRNAs down and three miRNAs upregulated). MiR-23a-3p, known to be involved in glioblastoma invasion, was significantly increased in 3D. MiR-7-5p, which counteracts glioblastoma malignancy, was significantly decreased. Moreover, we identified four miRNAs (miR- 323a-3p, miR-382-5p, miR-370-3p, miR-134-5p) located within the DLK1-DIO3 domain, a cancer associated genomic region, suggesting a possible importance of this region in glioblastoma progression. Overrepresentation analysis identified alterations of extracellular vesicle cargo in 3D organoids, including representation of several miRNA targets and proteins primarily implicated in the immune response.Conclusion: Our results show that 3D glioblastoma organoid models secrete extracellular vesicles with an altered cargo compared to corresponding conventional 2D cultures. Extracellular vesicles from 3D cultures were found to contain signaling molecules associated with the immune regulatory signaling pathways and as such could potentially change the surrounding microenvironment towards tumor progression and immunosuppressive conditions. These findings suggest the use of 3D glioblastoma models for further clinical biomarker studies as well as investigation of new therapeutic options.

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Unravelling the etiology of dilated cardiomyopathy through differential miRNA-mRNA interactome

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