Alternative Polyadenylation: Methods, Findings, and Impacts

Chen, Wei; Jia, Qi; Song, Yifan; Fu, Haihui; Wei, Gang; Ni, Ting

doi:10.1016/j.gpb.2017.06.001

Cited by 91 publications

(70 citation statements)

References 113 publications

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“…Clp1-driven shortening in mTEChi remains to be precisely defined. Current methods to 378 capture mTEChi-specific pAs using next generation sequencing methods require very large 379 numbers of cells relative to the number of mTEChi (~30,000) that can be isolated per mouse 380 but emerging methods for accurate pA identification with lower input requirements could 381 make this feasible from such low material quantity (W. Chen et al, 2017). 382 383 Clp1 is a member of the core 3' end processing complex that we showed to be 384 preferentially located at proximal pAs of Aire-sensitive genes in HEK293 cells, indicating that 385 the effect of Clp1 on 3'UTR shortening could result from enhanced recruitment of the 3' end 386 processing complex to proximal pAs.…”

Section: -Source Data 1) Comparison Of the Two Gene Sets 322mentioning

confidence: 99%

Aire-dependent genes undergo Clp1-mediated 3’UTR shortening associated with higher transcript stability in the thymus

Guyon¹,

Jmari

Padonou

et al. 2019

Preprint

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AbstractThe ability of the immune system to avoid autoimmune disease relies on tolerization of thymocytes to self-antigens whose expression and presentation by thymic medullary epithelial cells (mTECs) is controlled predominantly by Aire at the transcriptional level and possibly regulated at other unrecognized levels. Aire-sensitive gene expression is influenced by several molecular factors, some of which belong to the 3’end processing complex, suggesting they might impact transcript stability and levels through an effect on 3’UTR shortening. We discovered that Aire-sensitive genes display a pronounced preference for short-3’UTR transcript isoforms in mTECs, a feature preceding Aire’s expression and correlated with the preferential selection of proximal polyA sites by the 3’end processing complex. Through an RNAi screen and generation of a lentigenic mouse, we found that one factor, Clp1, promotes 3’UTR shortening associated with higher transcript stability and expression of Aire-sensitive genes, revealing a post-transcriptional level of control of Aire-activated expression in mTECs.

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Section: -Source Data 1) Comparison Of the Two Gene Sets 322mentioning

confidence: 99%

Aire-dependent genes undergo Clp1-mediated 3’UTR shortening associated with higher transcript stability in the thymus

Guyon¹,

Jmari

Padonou

et al. 2019

Preprint

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“…Therefore, understanding the regulation of gene expression and the corresponding regulatory networks is crucial to dissecting the mechanism of cellular senescence. Alternative polyadenylation (APA) is recognized as a crucial contributor to the regulation of mammalian gene expression (Di Giammartino et al 2011;Elkon et al 2013;Chen et al 2017;Tian and Manley 2017). Cleavage and polyadenylation of nascent RNA is essential for maturation of the vast majority of eukaryotic mRNAs and determines the length of 3 ′ UTRs (Sachs 1990).…”

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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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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“…Further enrichment analyses support that APA-derived, miRNA-mediated [41], [42] transcriptomic diversity contributes to interpatient difference in tumor progression. First, 911 genes targeted only by tamoMiRNAs include significantly more oncogenes than the same number of genes targeted by other miRNAs (43 vs. 28, P-value=0.03), suggesting that a varying degree of APA diversifies the effect of miRNA target activity on the oncogenic processes across tumor samples.…”

Section: Apa Regulates Tumor-specific Progression To Affect Interpatimentioning

confidence: 74%

Alternative Polyadenylation Regulates Patient-specific Tumor Growth by Individualizing the MicroRNA Target Site Landscape

Bai

Fan

et al. 2019

Preprint

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2Background: Alternative polyadenylation (APA) shortens or lengthens the 3ʹ-untranslated region (3ʹ-UTR) of hundreds of genes in cancer. While APA genes modify microRNA target sites in the 3ʹ-UTRs to promote tumorigenesis, previous studies have focused on a subset of the modification landscape. Method:For comprehensive understanding of the function of global APA events, we consider the total target site landscape of microRNAs that are significantly and collectively modified by global APA genes. To identify such microRNAs in spite of complex interactions between microRNAs and the APA genes, we developed Probabilistic Inference of MicroRNA Target Site Modification through APA (PRIMATA-APA). Results:Running PRIMATA-APA on TCGA breast cancer data, we identified that global APA events concentrate to modify target sites of particular microRNAs (target-site-modified-miRNA or tamoMiRNA). TamoMiRNAs are enriched for microRNAs known to regulate cancer etiology and treatments. Also, their target genes are enriched in cancer-associated pathways, suggesting that APA modifies target sites of tamoMiRNAs to progress tumors. Knockdown of NUDT21, a master 3ʹ-UTR regulator in HeLa cells, confirmed the causal role of tamoMiRNAs for tumor growth.Conclusions: Further, the expressions of tamoMiRNA target genes, enriched in cancerassociated pathways, vary across tumor samples as a function of patient-specific APA events, suggesting that APA is a novel regulatory axis for interpatient tumor heterogeneity. BackgroundThe dynamic usage of the messenger RNA 3ʹ-untranslated region (3ʹ-UTR) through alternative polyadenylation (APA) results in transcription of distinct isoforms with shortened or lengthened 3ʹ-UTRs. 3ʹ-UTR lengthening (3ʹUL) was recently reported to regulate cell senescence[1] linked with tumor suppressive pathways such as cell cycle inhibitors and DNA damage markers[2]-[5]. 3ʹ-UTR shortening (3ʹUS) was reported widespread in diverse types of human cancers[6]. Further, the impact of 3ʹUS on prognosis[6] and its association with drug sensitivity[7] suggests clinical implications of APA events in human cancer.We discovered a 3ʹUS trans tumorigenic mechanism[8] based on its interaction with competing-endogenous RNA (ceRNA) [9]. Since 3ʹUS removes microRNA (miRNA) target sites in the distal region of the 3ʹ-UTRs, genes with 3ʹUS event (3ʹUS genes) do not sequester the miRNAs. Since ceRNAs co-regulate each other RNAs through competing for binding miRNAs, the miRNAs released from 3ʹUS would be redirected to the ceRNA partners of the 3ʹUS genes, working to promote tumorigenesis. Recently, we also found that this interactive mechanism between 3ʹUS and ceRNA is involved in the subtype-specific progression of breast cancer [10].However, computational predictions of ceRNA have been limited for RNAs with >5 miRNA target sites [8], [9], [11], [12]. Since such RNAs account for a subset of all expressed genes (e.g. among 17,085 genes with the average HiSeqV2 expression value > 1 across 1,098 TCGA breast tumor samples, 5,258 genes (30.5 %) have...

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Alternative Polyadenylation: Methods, Findings, and Impacts

Cited by 91 publications

References 113 publications

Aire-dependent genes undergo Clp1-mediated 3’UTR shortening associated with higher transcript stability in the thymus

Aire-dependent genes undergo Clp1-mediated 3’UTR shortening associated with higher transcript stability in the thymus

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

Alternative Polyadenylation Regulates Patient-specific Tumor Growth by Individualizing the MicroRNA Target Site Landscape

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