Identification of Novel Mir-34a Targets in a c-Myc Murine Model

MicroRNAs (miRNAs) serve a fundamental function in the post-transcriptional regulation of gene expression. MiRNA-mediated repression is mediated by the RNA-induced silencing complex (RISC) and is generally thought to be predicted by base-pairing in the seed region of the microRNA. In predicting the effects of miRNAs on gene expression, it is important to consider that the transcriptional context will result in differential targeting of transcripts, and necessitates the study of miRNA function in the cell type of interest. Here, to study tumor suppressive functions of two miRNAs, miR-146a and miR-34a, we utilized the Eμ-Myc transgenic mouse bred to targeted knockouts for these two miRNAs. We found that miR-146a deficiency led to more aggressive B-cell neoplasms that showed a more differentiated B-cell phenotype. Transcriptional changes were fairly limited and were not enriched for miR-146a targets as a class. However, the changes included differences that were consistent with regulation of the transcription factor Egr1, which was demonstrated to be a direct target in human cells. In miR-34a deficient mice with the Eμ-Myc transgene, we did not observe changes in survival or in the phenotype of the neoplasms that developed. However, transcriptional profiling revealed changes in many predicted miR-34a targets, as determined by gene set enrichment analyses (GSEA). Novel predicted targets are being analyzed by luciferase assays. These analyses reveal the importance of assessing cell-type and disease-specific miRNA targeting, which can reveal novel and previously unknown miRNA targets and facilitate our understanding of leukemia and lymphoma pathogenesis.