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Series GSE201308 Query DataSets for GSE201308
Status Public on Dec 08, 2022
Title Monitoring the 5′UTR landscape reveals isoform switches to drive translational efficiencies in cancer [CAGE-seq]
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Transcriptional and translational control are key determinants of gene expression, however, to what extent these two processes can be collectively coordinated is still poorly understood. Here, we use Nanopore long-read sequencing and cap analysis of gene expression (CAGE-seq) to document the landscape of 5′ and 3′ untranslated region (UTR) isoforms and transcription start sites of epidermal stem cells, wild-type keratinocytes and squamous cell carcinomas. Focusing on squamous cell carcinomas, we show that a small cohort of genes with alternative 5′UTR isoforms exhibit overall increased translational efficiencies and are enriched in ribosomal proteins and splicing factors. By combining polysome fractionations and CAGE-seq, we further characterize two of these UTR isoform genes with identical coding sequences and demonstrate that the underlying transcription start site heterogeneity frequently results in 5′ terminal oligopyrimidine (TOP) and pyrimidine-rich translational element (PRTE) motif switches to drive mTORC1-dependent translation of the mRNA. Genome-wide, we show that highly translated squamous cell carcinoma transcripts switch towards increased use of 5′TOP and PRTE motifs, have generally shorter 5′UTRs and expose decreased RNA secondary structures. Notably, we found that the two 5′TOP motif-containing, but not the TOP-less, RPL21 transcript isoforms strongly correlated with overall survival in human head and neck squamous cell carcinoma patients. Our findings warrant isoform-specific analyses in human cancer datasets and suggest that switching between 5′UTR isoforms is an elegant and simple way to alter protein synthesis rates, set their sensitivity to the mTORC1-dependent nutrient-sensing pathway and direct the translational potential of an mRNA by the precise 5′UTR sequence.
Overall design RNA from mouse P56-60 epidermis, cultured WT and HRASG12V; TGFBR-2 KO keratinocytes was isolated and used for cap analysis of gene expression (CAGE sequencing).
Contributor(s) Weber R, Sendoel A
Citation(s) 36550360
Submission date Apr 22, 2022
Last update date Mar 10, 2023
Contact name Ramona Weber
Organization name University of Zurich
Department Institute for Regenerative Medicine
Street address Wagistrasse 12
City Schlieren
ZIP/Postal code 8952
Country Switzerland
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (11)
GSM6058065 CAGE-seq P60 EpSC
GSM6058066 CAGE-seq WT
GSM6058067 CAGE-seq HrasG12V; Tgfbr2 KO (SCC)
BioProject PRJNA830854

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Supplementary file Size Download File type/resource
GSE201308_RAW.tar 101.7 Mb (http)(custom) TAR (of BIGWIG)
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Raw data are available in SRA
Processed data provided as supplementary file

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