Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3′-UTR landscape across seven tumour types

Xia, Zheng; Donehower, Lawrence A.; Cooper, Thomas A.; Neilson, Joel R.; Wheeler, David A.; Wagner, Eric J.; Li, Wei

doi:10.1038/ncomms6274

Cited by 453 publications

(712 citation statements)

References 56 publications

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“…recent findings that up-regulation of polyadenylation factors was associated with 3 ′ UTR shortening (Mayr and Bartel 2009;Xia et al 2014). These results provided a possible mechanistic explanation for 3 ′ UTR lengthening during cellular senescence and deserved further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, both microRNAs (miRNAs) and RNA binding proteins (RBPs) targeting 3 ′ UTRs are able to regulate translational efficiency, degradation, and subcellular localization of mRNA or protein (Di Giammartino et al 2011;Berkovits and Mayr 2015;Tian and Manley 2017). It is well known that APA plays important roles in a wide range of biological processes such as cell differentiation (Ji et al 2009;Mangone et al 2010;Hilgers et al 2011;Ulitsky et al 2012;Fu et al 2016;Hu et al 2017), cell proliferation Elkon et al 2012;Hoffman et al 2016), cell/tissue identity Derti et al 2012;Smibert et al 2012;Ni et al 2013), and carcinogenesis (Mayr and Bartel 2009;Fu et al 2011;Lin et al 2012;Xia et al 2014). However, whether APA is involved in senescenceassociated gene expression and contributes to cellular senescence remains to be answered.…”

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confidence: 99%

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3′ UTR lengthening as a novel mechanism in regulating cellular senescence

Chen¹,

Lyu

Han³

et al. 2018

Genome Res.

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Cellular senescence has been viewed as a tumor suppression mechanism and also as a contributor to individual aging. Widespread shortening of 3 ′ untranslated regions (3 ′ UTRs) in messenger RNAs (mRNAs) by alternative polyadenylation (APA) has recently been discovered in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. Here, we found that hundreds of genes in senescent cells tended to use distal poly(A) (pA) sites, leading to a global lengthening of 3 ′ UTRs and reduced gene expression. Genes that harbor longer 3 ′ UTRs in senescent cells were enriched in senescence-related pathways. Rras2, a member of the Ras superfamily that participates in multiple signal transduction pathways, preferred longer 3 ′ UTR usage and exhibited decreased expression in senescent cells. Depletion of Rras2 promoted senescence, while rescue of Rras2 reversed senescence-associated phenotypes. Mechanistically, splicing factor TRA2B bound to a core "AGAA" motif located in the alternative 3 ′ UTR of Rras2, thereby reducing the RRAS2 protein level and causing senescence. Both proximal and distal poly(A) signals showed strong sequence conservation, highlighting the vital role of APA regulation during evolution. Our results revealed APA as a novel mechanism in regulating cellular senescence.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

3′ UTR lengthening as a novel mechanism in regulating cellular senescence

Chen¹,

Lyu

Han³

et al. 2018

Genome Res.

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“…To determine whether reduced U1 snRNA levels in our snRNP biogenesis mutants correlated with expression of shorter mRNAs, mapped RNA-seq reads were analyzed using the DaPars linear regression algorithm (Masamha et al 2014;Xia et al 2014). DaPars output is displayed as a percentage of distal poly(A) site usage index (PDUI) for each transcript, or as the difference in the PDUI value between wild-type and mutant (ΔPDUI).…”

Section: Snrnp Biogenesis Mutants Exhibit a Trend Toward Shorter Mrnasmentioning

confidence: 99%

“…TopHat and Cufflinks were used for gene expression analyses, according to the bioinformatic pipeline from Trapnell et al (2012). DaPars was used to identify differences in RNA length and alternative polyadenylation (Masamha et al 2014;Xia et al 2014). MISO (Katz et al 2010) was used to measure changes in annotated alternative-splicing events.…”

Section: Rna-seq and Bioinformatics Analysesmentioning

confidence: 99%

Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy

Garcia

Wen

Praveen

et al. 2016

RNA

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Survival motor neuron (SMN) functions in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) that catalyze pre-mRNA splicing. Here, we used disruptions in Smn and two additional snRNP biogenesis genes, Phax and Ars2, to classify RNA processing differences as snRNP-dependent or gene-specific in Drosophila. Phax and Smn mutants exhibited comparable reductions in snRNAs, and comparison of their transcriptomes uncovered shared sets of RNA processing changes. In contrast, Ars2 mutants displayed only small decreases in snRNA levels, and RNA processing changes in these mutants were generally distinct from those identified in Phax and Smn animals. Instead, RNA processing changes in Ars2 mutants support the known interaction of Ars2 protein with the cap-binding complex, as splicing changes showed a clear bias toward the first intron. Bypassing disruptions in snRNP biogenesis, direct knockdown of spliceosomal proteins caused similar changes in the splicing of snRNP-dependent events. However, these snRNP-dependent events were largely unaltered in three Smn mutants expressing missense mutations that were originally identified in human spinal muscular atrophy (SMA) patients. Hence, findings here clarify the contributions of Phax, Smn, and Ars2 to snRNP biogenesis in Drosophila, and loss-of-function mutants for these proteins reveal differences that help disentangle cause and effect in SMA model flies.

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“…While APA can be analyzed with data from microarrays , serial analysis of gene expression (SAGE) ) or RNA-seq (Katz et al 2010;Xia et al 2014), these techniques were not specifically designed to identify pAs, leading to incomplete analysis. These methods are particularly ineffective when pAs of different isoforms are located close to one another.…”

Section: Introductionmentioning

confidence: 99%

3′READS+, a sensitive and accurate method for 3′ end sequencing of polyadenylated RNA

Zheng

Liu

Tian

2016

RNA

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Sequencing of the 3 ′ end of poly(A) + RNA identifies cleavage and polyadenylation sites (pAs) and measures transcript expression. We previously developed a method, 3′ region extraction and deep sequencing (3 ′ READS), to address mispriming issues that often plague 3′ end sequencing. Here we report a new version, named 3 ′ READS+, which has vastly improved accuracy and sensitivity. Using a special locked nucleic acid oligo to capture poly(A) + RNA and to remove the bulk of the poly(A) tail, 3 ′ READS+ generates RNA fragments with an optimal number of terminal A's that balance data quality and detection of genuine pAs. With improved RNA ligation steps for efficiency, the method shows much higher sensitivity (over two orders of magnitude) compared to the previous version. Using 3 ′ READS+, we have uncovered a sizable fraction of previously overlooked pAs located next to or within a stretch of adenylate residues in human genes and more accurately assessed the frequency of alternative cleavage and polyadenylation (APA) in HeLa cells (∼50%). 3 ′ READS+ will be a useful tool to accurately study APA and to analyze gene expression by 3 ′ end counting, especially when the amount of input total RNA is limited.

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Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3′-UTR landscape across seven tumour types

Cited by 453 publications

References 56 publications

3′ UTR lengthening as a novel mechanism in regulating cellular senescence

3′ UTR lengthening as a novel mechanism in regulating cellular senescence

Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy

3′READS+, a sensitive and accurate method for 3′ end sequencing of polyadenylated RNA

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