MicroRNA And Transcription Factor Regulatory Network Analysis In Myocardial Infarction And Ventricular Remodeling

Myocardial infarction (MI) is a leading cause of death in the industrialized world, and thusdevelopment of new therapeutic strategies is an important aim of both clinical and basiccardiovascular research. Many genes and biological processes were reported to beinvolved in MI and the regulation in MI is very complex. Here, we pursued a regulatorynetwork-based approach for the comprehensive investigation of gene regulation patterns inMI. Firstly, we compiled MI related genes and miRNAs from multiple sources; PUBMED,CADgene, GWAS, HMDD and miR2disease, which included multiple types of variationswith experimental proof. Then, we identified the potential regulatory relations for TF-MIgenes/miRNAs and MI miRNAs-MI genes/TFs. For the TF-MI genes/miRNAs, weretrieved predicted transcription factor binding site (TFBS) information from the UCSCgenome browser (hg18) and obtained the verified TF targets from TRANSFAC databaseand ChIP-seq data which were downloaded from ENCODE project and NCBI GEODataSets. Predicted and experimentally verified miRNA targets were obtained fromTargetScan, miRanda and miR2Disease, miRTarBase, miRecords and TarBase databasesrespectively. Using an in-house script, these regulatory relations were used to construct acomprehensive MI-specific miRNA-TF mediated regulatory network which consisted of2,382merged FFLs;1424(59.8%) belonged to TF-FFLs,815(34.2%) belonged tomiRNA-FFLs, and143(6%) belonged to composite-FFLs. We then constructed the post-MI regulatory sub network in order to investigate regulators in ventricular remodeling. Acomparison between the MI miRNA-TF regulatory network hubs and the post-MI subnetwork hubs revealed overlapping hubs which comprised of;3genes (VEGFA, PTENand PRKCE),3miRNAs (miR-1, miR-21-5p, and miR-26b-5p) and5TFs (EGR1, JUN,MAZ, SP1and YY1). It is our hypothesis that these elements may play essential roles inboth MI-incidence and post-MI cardiac remodeling. We selected an enriched core pathwayamong our MI candidate genes; the NFAT and Hypertrophy of the heart signalingpathway and identified functionally critical miRNAs in this pathway. Finally a cellularmodel of the major miRNAs/TFs and their targets involved in signaling pathways wasconstructed and we proposed that miR-1acts as a switch in MI progression and that either up or down regulation has the potential to provide a powerful regulatory tool forcardiomyocyte self-renewal and differentiation, as well as for normal cardiac morphology.Our network offers detailed information about the molecular mechanism by whichcandidate miRNA/genes lead to MI and also the role of these genes and their regulators incardiac remodeling, thus shedding more light on potential treatment targets.