Monitoring the 5′UTR landscape reveals isoform switches to drive translational efficiencies in cancer

Our recent publication in Oncogene documents the 5' and 3' UTR landscape of messenger RNAs expressed in three different cell types of the skin: epidermal stem cells, wild-type keratinocytes and squamous cell carcinoma. The datasets are available in the UCSC genome browser for common access.
Monitoring the 5′UTR landscape reveals isoform switches to drive translational efficiencies in cancer
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In our study 'Monitoring the 5′UTR landscape reveals isoform switches to drive translational efficiencies in cancer' we used Nanopore long-read sequencing and cap analysis of gene expression (CAGE-seq) to documents the 5' and 3' untranslated region (UTR) landscape of epidermal stem cells, wild-type keratinocytes and squamous cell carcinoma. To serve as a resource, we made the datasets publicly available in the UCSC genome browser under the following link: 

5' UTR landscape data browser

These datasets will allow you to 1. check out the isoform usage of your favorite gene by browsing the Oxford Nanopore Technology (ONT) datasets (Nanopore long-read sequencing) in different cell types of the skin: epidermal stem cells (EpSC), wild-type keratinocytes (Keratinocytes) and squamous cell carcinoma (SCC);

2. assess the exact 5' end and heterogeneity of transcription start site usage by the CAGE-seq data mapping to the negative and positive strand of the reference genome (e.g. EpSC neg and EpSC pos);

3. analyse how the 5' transcription start site tunes the translational efficiency of the mRNA isoform by the CAGE-seq data in LP (low polysomes=inefficiently translated) and HP (high polysomes=efficiently translated);

4. identify the 5' transcription start site isoforms that are most efficiently translated (ratio HP vs LP).


Summary

A genome-wide analysis of our data showed that squamous cell carcinoma and epidermal stem cells  compared to wild-type keratinocytes  express numerous alternative mRNA isoforms, many of them encoding 5' terminal oligopyrimidine (TOP) mRNAs, e.g. ribosomal protein mRNAs. Focussing on squamous cell carcinoma, we find that a specific cohort of genes switch towards an increased use of 5'TOP and pyrimidine-rich translational element (PRTE) motifs to drive efficient and mTORC1-dependent translation of the 5'UTR isoforms with identical coding sequences. This heterogeneity in transcription start site usage of 5'TOP motif-containing mRNAs represents a simple but effective way to tune the translational efficiency of these mRNAs and their sensitivity to the mTORC1-dependent nutrient-sensing pathway without changing the protein's primary sequence. Notably, we found that 5'TOP motif-containing, but not the TOP-less, RPL21 transcript isoform expression strongly correlates with overall survival in human head and neck squamous cell carcinoma patients. These findings warrant isoform-specific analyses in human cancer datasets and highlight the role of translational control during cancer formation.

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