Identification and analysis of the regulatory network of Myc and microRNAs from high-throughput experimental data

Abstract

As a transcription factor, c-Myc exerts significant influence in cancer development by regulating transcription of a large number of target genes including microRNAs. However, details of regulatory networks composed of Myc, microRNAs, and microRNA target genes are still unclear. Here, at system level, we built a comprehensive Myc-regulated miRNAs (Myc-miRNAs) regulatory network through the integration of experimentally validated high-throughput data and computational predictions. Using miRNA genomic information with ChIP-PET, we identified 30 Myc-miRNAs and found most of these Myc-miRNAs target genes were significantly enriched in cell cycle, apoptosis, cell proliferation GO terms and Myc-regulated signaling pathways, using gene sets enrichment analysis. We found most Myc-miRNAs involved in Myc-related cancer pathways expressed abnormally in Myc-associated tumors through the integration of diverse types of experimental data. Based upon Myc target genes identified by ChIP-chip assays, we identified that 1031 Myc-miRNAs feed-forward loops (FFLs) were significantly different from those obtained by chance; also, 11 high-quality FFLs were extracted from experimentally validated interactions. Finally, we built the miRNA-protein interaction network of experimentally validated Myc-miRNAs and discussed the more complex network composed of several FFLs networks. As shown in this study, we performed comprehensive analysis of the Myc-miRNAs regulatory network and provided potential Myc-miRNAs target genes which were involved in Myc pathway and cancer-related biological processes.

Keywords: Microrna; Myc; Network; Signaling pathways.