Genome-scale Modeling of Regulatory Networks that Govern mRNA Stability and their Implication in Cancer
Department of Human Genetics, McGill University; McGill University and Genome Quebec Innovation Center
Background: The regulation of mRNA decay is a major mechanism of post-transcriptional modulation of gene expression. mRNA stability is largely regulated by the binding of RNA- binding proteins (RBPs) and micro-RNAs (miRNAs) to specific regulatory sequences or secondary structures within mRNAs. Several types of cancer are associated with changes in mRNA stability.
Rationale: Specific factors regulating mRNA stability have been implicated in transcriptome remodeling in cancer and have causal roles in tumorigenesis, but a systematic investigation of the mechanisms leading to the dysregulation of mRNA stability has not yet been performed.
Methods: Using newly developed computational methods that estimate mRNA stability from RNA-seq data, we performed a pan-cancer analysis of genome-wide mRNA stability profiles across patient tumor and normal tissue samples. We combined stability profiles with miRNA regulatory networks to infer changes in their activity in tumors. A similar approach was used to identify RBPs with modulated activity in renal cell carcinoma specifically. Candidate RBPs were experimentally validated using RNA-seq data from knockdown experiments in renal cell carcinoma cell lines.
Results: We have identified miRNAs that potentially drive cancer-associated mRNA stability signatures, including broadly dysregulated miRNAs such as miR-29, miRNAs including miR- 124 that are specific to one or few cancer types, and miRNAs such as miR-200 that are specific to cancer subtypes. The activity of many of these dysregulated miRNAs has prognostic potential, as it was associated with significant differences in patient survival, tumor grade/stage and metastasis. Focusing on the factors that modulate mRNA stability in renal cell carcinoma, we identified and validated three RBPs (ESRP2, PCBP2 and MBNL2) that play a major role in shaping the cancer transcriptome and regulating pathways such as hypoxia signaling and cell cycle.
Significance: The stability regulation models generated through this project provide new insights into the post-transcriptional mechanisms involved in cancer transcriptome remodeling.