Dataset Information

Genome-wide profiling reveals alternative polyadenylation of mRNA in human non-small cell lung cancer.

ABSTRACT:

Background

Lung cancer is the second most common cancer with an extremely poor overall survival rate. Post-transcriptional regulation of gene expression play many important roles in human cancer, and one of the potential mechanisms underlying this is alternative mRNA maturation at its 3' untranslated regions (3'-UTRs).

Methods

Cancer tissues and paired adjacent normal lung tissues from 26 patients diagnosed with non-small cell lung cancer (NSCLC) were analyzed by in vitro transcription-sequencing alternative polyadenylation sites (IVT-SAPAS). 41,773,101 reads in average were obtained from each paired sample. A potential regulation of Cleavage Stimulation Factor Subunit 2 (CSTF2) on 3'UTR length of genes was tested in H460 cells.

Results

1439 (10.26%) genes showed up-regulated expression and 1364 (9.72%) genes showed down-regulated expression in lung cancer tissue versus normal lung tissue, and shorten 3'UTR in cancer tissue was detected in cancer tissues collected from 96.2% (25/26) patients, indicating lung cancer tend to have shortened 3'UTRs of these identified genes. KEGG analysis showed 1855 genes with shorten 3'UTR were enriched in mTOR signaling, ubiquitin mediated proteolysis and RNA degradation. Knocking down CSTF2 expression in H460 cells results in 3'UTR elongation of genes that was identified to be with shortened length in cancer tissues.

Conclusion

Alternative polyadenylation (APA) site-switching of 3'UTRs is prevalent in NSCLC, and CSTF2 may serve as an oncogene regulates the 3'UTR length of cancer related genes in NSCLC.

SUBMITTER: Zhang S

PROVIDER: S-EPMC6686416 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Genome-wide profiling reveals alternative polyadenylation of mRNA in human non-small cell lung cancer.

Zhang Shirong S Zhang Xiaochen X Lei Wei W Liang Jiafeng J Xu Yasi Y Liu Hailiang H Ma Shenglin S

Journal of translational medicine 20190807 1

<h4>Background</h4>Lung cancer is the second most common cancer with an extremely poor overall survival rate. Post-transcriptional regulation of gene expression play many important roles in human cancer, and one of the potential mechanisms underlying this is alternative mRNA maturation at its 3' untranslated regions (3'-UTRs).<h4>Methods</h4>Cancer tissues and paired adjacent normal lung tissues from 26 patients diagnosed with non-small cell lung cancer (NSCLC) were analyzed by in vitro transcri ...[more]

PMID: 31391087

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Project description:MotivationPre-mRNA cleavage and polyadenylation are essential steps for 3'-end maturation and subsequent stability and degradation of mRNAs. This process is highly controlled by cis-regulatory elements surrounding the cleavage/polyadenylation sites (polyA sites), which are frequently constrained by sequence content and position. More than 50% of human transcripts have multiple functional polyA sites, and the specific use of alternative polyA sites (APA) results in isoforms with variable 3'-untranslated regions, thus potentially affecting gene regulation. Elucidating the regulatory mechanisms underlying differential polyA preferences in multiple cell types has been hindered both by the lack of suitable data on the precise location of cleavage sites, as well as of appropriate tests for determining APAs with significant differences across multiple libraries.ResultsWe applied a tailored paired-end RNA-seq protocol to specifically probe the position of polyA sites in three human adult tissue types. We specified a linear-effects regression model to identify tissue-specific biases indicating regulated APA; the significance of differences between tissue types was assessed by an appropriately designed permutation test. This combination allowed to identify highly specific subsets of APA events in the individual tissue types. Predictive models successfully classified constitutive polyA sites from a biologically relevant background (auROC = 99.6%), as well as tissue-specific regulated sets from each other. We found that the main cis-regulatory elements described for polyadenylation are a strong, and highly informative, hallmark for constitutive sites only. Tissue-specific regulated sites were found to contain other regulatory motifs, with the canonical polyadenylation signal being nearly absent at brain-specific polyA sites. Together, our results contribute to the understanding of the diversity of post-transcriptional gene regulation.AvailabilityRaw data are deposited on SRA, accession numbers: brain SRX208132, kidney SRX208087 and liver SRX208134. Processed datasets as well as model code are published on our website: http://www.genome.duke.edu/labs/ohler/research/UTR/.Contactuwe.ohler@duke.edu.

Dataset Information

Genome-wide profiling reveals alternative polyadenylation of mRNA in human non-small cell lung cancer.

Background

Methods

Results

Conclusion

Publications

Genome-wide profiling reveals alternative polyadenylation of mRNA in human non-small cell lung cancer.

Similar Datasets

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