Fine-tuning of microRNA-mediated repression of mRNA by splicing-regulated and highly repressive microRNA recognition element

• Main Authors: Cheng-Tao Wu, 吳政道
• Other Authors: Ueng-Cheng Yang
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/80723235116173982758

博士 === 國立陽明大學 === 生物醫學資訊研究所 === 102 === MicroRNAs are very small non-coding RNAs that interact with microRNA recognition elements (MREs) on their target messenger RNAs. Varying the concentration of a given microRNA may influence the expression of many target proteins. Yet, the expression of a specific target protein can be fine-tuned by alternative cleavage and polyadenylation to the corresponding mRNA. This study shows that alternative splicing of mRNA is a fine-tuning mechanism in the cellular regulatory network. The splicing-regulated MREs are often highly repressive MREs. We demonstrate that this phenomenon is observed not only in the hsa-miR-148a-regulated DNMT3B gene, but also in many target genes regulated by hsa-miR-124, hsa-miR-1, and hsa-miR-181a. When a gene contains multiple MREs in transcripts, such as the VEGF gene, the splicing-regulated MREs are again the highly repressive MREs. We also present evidence that approximately one-third of the analysable human MREs in MiRTarBase and TarBase can potentially perform the splicing-regulated fine-tuning. Interestingly, the high (+30%) repression ratios observed in most of these splicing-regulated MREs indicate associations with functions. For example, the MRE-free transcripts of many oncogenes, such as N-RAS and others may escape microRNA-mediated suppression in cancer tissues. This fine-tuning mechanism revealed associations with highly repressive MRE. Since high-repression MREs are involved in many important biological phenomena, the described association implies that splicing-regulated MREs are functional. A possible application of this observed association is in distinguishing functionally relevant MREs from predicted MREs.