Microrna 9 upregulation integrates post ischemic neuronal survival and regeneration a systems biology approach

Abstract

The complex and interlinked cascade of events regulated by microRNAs (miRNAs), transcription newlinefactors (TFs) and target genes highlight the multifactorial nature of ischemic stroke pathology. The newlinecomplexity of ischemic stroke requires a broader assessment than the existing experimental research newlinethat deals with only a few regulatory components. In this study, a massive set of genes, miRNAs, and newline newlineTFs were assessed to build a miRNA-gene-TF regulatory network specific for ischemic stroke. Feed- newlineforward loops (FFLs) [3-node, 4-node, and novel 5-node] were formed and converged to establish newline newlineregulatory interactions between miRNAs, TFs and genes. The synergistic function of miRNAs in newlineischemic stroke was predicted and incorporated into the novel 5-node FFL. Significant miRNA-TF newlinepairs were identified using cumulative hypergeometric distribution. Two subnetworks were derived, newlinewhere nuclear factor kappa-light-chain-enhancer of activated B cells (NFand#954;B) and signal transducer newlineand activator of transcription (STAT) emerged as the chief regulators of innate inflammatory and newlineneuronal survival mechanism, respectively. The process-specific efficiency of 5-node FFL was newline newlinestudied by predicting core regulatory miRNAs in post-stroke neurogenesis, one of the most sought- newlineafter processes involved in ischemic stroke recovery. Exclusive network interactions between miR-9, newline newlinemiR-124, histone deacetylase-4 (HDAC4), B-cell lymphoma 2 (BCL2) and Protein Tailless Homolog newline(TLX) in post-stroke induced neurogenesis were identified. newlineThe systems-level prediction of miR-9 in post-stroke induced neurogenesis served as a premise to newlineexperimentally uncover the functional role of miR-9 in post-ischemic neuronal survival and newline newlineregeneration. The oxygen-glucose deprivation (OGD) in primary neural progenitor stem cells and SH- newlineSY5Y cell line significantly reduced miR-9 expression. While it was observed that miR-9 mimic newline newlinetransfection enhanced post-ischemic neuronal cell viability.