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Abstract
The functional consequences of genetic variants within 5’ untranslated regions (UTRs) on a genome-wide scale are poorly understood in disease. Here we develop a high-throughput multi-layer functional genomics method called PLUMAGE (Pooled full-length UTR Multiplex Assay on Gene Expression) to quantify the molecular consequences of somatic 5’ UTR mutations in human prostate cancer. We show that 5’ UTR mutations can control transcript levels and mRNA translation rates through the creation of DNA binding elements or RNA-based cis-regulatory motifs. We discover that point mutations can simultaneously impact transcript and translation levels of the same gene. We provide evidence that functional 5’ UTR mutations in the MAP kinase signaling pathway can upregulate pathway-specific gene expression and are associated with clinical outcomes. Our study reveals the diverse mechanisms by which the mutational landscape of 5’ UTRs can co-opt gene expression and demonstrates that single nucleotide alterations within 5’ UTRs are functional in cancer.
Highlights
The functional consequences of genetic variants within 5’ untranslated regions (UTRs) on a genome-wide scale are poorly understood in disease
To determine if these 5′-untranslated region (5′-UTR) mutations were associated with changes in gene expression, we compared biological replicates of each LuCaP xenograft to a cohort of normal prostate tissues of high glandularity using human tissue-based transcriptome analysis and ribosome profiling (Supplementary Figs. 2 and 3a and Supplementary Data 1b, c)[24,25]
Given that our tissue-based studies only provide an association between 5′-UTR mutations and gene expression changes, and that these changes could be caused by other types of genetic
Summary
The functional consequences of genetic variants within 5’ untranslated regions (UTRs) on a genome-wide scale are poorly understood in disease. Transcribed 5′-UTRs are composed of a variety of RNA-based regulatory elements including the 5′-cap structure, secondary structures, RNA-binding protein motifs, upstream open-reading frames (uORFs), internal ribosome entry sites, terminal oligo pyrimidine (TOP) tracts, and G-quadruplexes These elements can alter the efficiency of mRNA translation[3]; some can affect mRNA transcript levels via changes in stability or degradation[4]. Parallel reporter assays (MPRAs) have been employed to dissect the functional consequences of genetic variation in regulatory elements such as promoters and enhancers[12,13] These high-throughput technologies have enabled the characterization of these genomic regions on transcriptional activities. This approach has been used to study UTR elements and their effects on mRNA degradation and translation[14,15,16,17]. No studies to date have determined the functional landscape of 5′-
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