Dataset Information

From miRNA Target Gene Network to miRNA Function: miR-375 Might Regulate Apoptosis and Actin Dynamics in the Heart Muscle via Rho-GTPases-Dependent Pathways.

ABSTRACT: MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, which are involved in the regulation of main biological processes, such as apoptosis or cell proliferation and differentiation, through sequence-specific interaction with target mRNAs. In this study, we propose a workflow for predicting miRNAs function by analyzing the structure of the network of their target genes. This workflow was applied to study the functional role of miR-375 in the heart muscle (myocardium), since this miRNA was previously shown to be associated with heart diseases, and data on its function in the myocardium are mostly unclear. We identified PIK3CA, RHOA, MAPK3, PAFAH1B1, CTNNB1, MYC, PRKCA, ERBB2, and CDC42 as key genes in the miR-375 regulated network and predicted the possible function of miR-375 in the heart muscle, consisting mainly in the regulation of the Rho-GTPases-dependent signaling pathways. We implemented our algorithm for miRNA function prediction into a Python module, which is available at GitHub.

SUBMITTER: Osmak G

PROVIDER: S-EPMC7765785 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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From miRNA Target Gene Network to miRNA Function: miR-375 Might Regulate Apoptosis and Actin Dynamics in the Heart Muscle via Rho-GTPases-Dependent Pathways.

Osmak German G Kiselev Ivan I Baulina Natalia N Favorova Olga O

International journal of molecular sciences 20201218 24

MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, which are involved in the regulation of main biological processes, such as apoptosis or cell proliferation and differentiation, through sequence-specific interaction with target mRNAs. In this study, we propose a workflow for predicting miRNAs function by analyzing the structure of the network of their target genes. This workflow was applied to study the functional role of miR-375 in the heart muscle (myo ...[more]

PMID: 33352947

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Project description:BackgroundPrevious research demonstrated that small Rho GTPases, modulators of the actin cytoskeleton, are drivers of podocyte foot-process effacement in glomerular diseases, such as FSGS. However, a comprehensive understanding of the regulatory networks of small Rho GTPases in podocytes is lacking.MethodsWe conducted an analysis of podocyte transcriptome and proteome datasets for Rho GTPases; mapped in vivo, podocyte-specific Rho GTPase affinity networks; and examined conditional knockout mice and murine disease models targeting Srgap1. To evaluate podocyte foot-process morphology, we used super-resolution microscopy and electron microscopy; in situ proximity ligation assays were used to determine the subcellular localization of the small GTPase-activating protein SRGAP1. We performed functional analysis of CRISPR/Cas9-generated SRGAP1 knockout podocytes in two-dimensional and three-dimensional cultures and quantitative interaction proteomics.ResultsWe demonstrated SRGAP1 localization to podocyte foot processes in vivo and to cellular protrusions in vitro. Srgap1fl/fl*Six2Cre but not Srgap1fl/fl*hNPHS2Cre knockout mice developed an FSGS-like phenotype at adulthood. Podocyte-specific deletion of Srgap1 by hNPHS2Cre resulted in increased susceptibility to doxorubicin-induced nephropathy. Detailed analysis demonstrated significant effacement of podocyte foot processes. Furthermore, SRGAP1-knockout podocytes showed excessive protrusion formation and disinhibition of the small Rho GTPase machinery in vitro. Evaluation of a SRGAP1-dependent interactome revealed the involvement of SRGAP1 with protrusive and contractile actin networks. Analysis of glomerular biopsy specimens translated these findings toward human disease by displaying a pronounced redistribution of SRGAP1 in FSGS.ConclusionsSRGAP1, a podocyte-specific RhoGAP, controls podocyte foot-process architecture by limiting the activity of protrusive, branched actin networks. Therefore, elucidating the complex regulatory small Rho GTPase affinity network points to novel targets for potentially precise intervention in glomerular diseases.

Dataset Information

From miRNA Target Gene Network to miRNA Function: miR-375 Might Regulate Apoptosis and Actin Dynamics in the Heart Muscle via Rho-GTPases-Dependent Pathways.

Publications

From miRNA Target Gene Network to miRNA Function: miR-375 Might Regulate Apoptosis and Actin Dynamics in the Heart Muscle via Rho-GTPases-Dependent Pathways.

Similar Datasets

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