RNA structural analysis of the MYC mRNA reveals conserved motifs that affect gene expression

Abstract

The MYC gene encodes a human transcription factor and proto-oncogene that is dysregulated in over half of all known cancers. To better understand potential post-transcriptional regulatory features affecting MYC expression, we analyzed secondary structures in the MYC mRNA using a program that is optimized for finding small locally-folded motifs with a high propensity for function. This was accomplished by calculating folding metrics across the MYC sequence using a sliding analysis window and generating unique consensus base pairing models weighted by their lower-than-random predicted folding energy. A series of 30 motifs were identified, primarily in the 5’ and 3’ untranslated regions, which show evidence of structural conservation and compensating mutations across vertebrate MYC homologs. This analysis was able to recapitulate known elements found within an internal ribosomal entry site, as well as discover a novel element in the 3’ UTR that is unusually stable and conserved. This novel motif was shown to affect MYC expression, potentially via the modulation of miRNA target accessibility or other trans-regulatory factors. In addition to providing basic insights into mechanisms that regulate MYC expression, this study provides numerous, potentially druggable RNA targets for the MYC gene, which is considered “undruggable” at the protein level.