Poly(A) code analyses reveal key determinants for tissue-specific mRNA alternative polyadenylation

Weng, Lingjie; Li, Yang; Xie, Xiaohui; Shi, Yongsheng

doi:10.1261/rna.055681.115

Cited by 19 publications

(23 citation statements)

References 38 publications

(68 reference statements)

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“…Prior work indicated that APA events are often regulated in a tissue-specific manner (Zhang et al, 2005) (Weng et al, 2016) (Lianoglou et al, 2013). Although compelling, these previous studies examined only a few tissue types with a relatively small sample size.…”

Section: Resultsmentioning

confidence: 99%

Genetic Basis of Alternative Polyadenylation is an Emerging Molecular Phenotype for Human Traits and Diseases

Gao

Peng

et al. 2019

Preprint

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SUMMARYGenome-wide association studies have identified thousands of non-coding variants that are statistically associated with human traits and diseases. However, functional interpretation of these variants remains a major challenge. Here, we describe the first atlas of human 3’-UTR alternative polyadenylation (APA) Quantitative Trait Loci (3’QTLs), i.e. ∼0.4 million genetic variants associated with APA of target genes across 46 Genotype-Tissue Expression (GTEx) tissues from 467 individuals. APA occurs in approximately 70% of human genes and substantively impacts cellular proliferation, differentiation and tumorigenesis. Mechanistically, 3’QTLs could alter polyA motifs and RNA-binding protein binding sites, leading to thousands of APA changes. Importantly, 3’QTLs can be used to interpret ∼16.1% of trait-associated variants and are largely distinct from other QTLs such as eQTLs. The genetic basis of APA (3’QTLs) thus represent a novel molecular phenotype to explain a large fraction of non-coding variants and to provide new insights into complex traits and disease etiologies.HighlightsThe first atlas of human 3’QTLs: ∼0.4 million genetic variants associated with alternative polyadenylation of target genes across 46 tissues from 467 individuals3’QTLs could alter polyA motifs and RNA-binding protein binding sites3’QTLs can be used to interpret ∼16.1% of trait-associated variantsMany disease-associated 3’QTLs contribute to phenotype independent of gene expression

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Section: Resultsmentioning

confidence: 99%

Genetic Basis of Alternative Polyadenylation is an Emerging Molecular Phenotype for Human Traits and Diseases

Gao

Peng

et al. 2019

Preprint

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“…The A[A/U]UAAA was more degenerate in Saccharomyces cerevisiae (Graber et al 1999), and the UGUG motif appears to be restricted to vertebrates (Tian and Graber 2012). The PAS motifs determine the strength of a PAS in a combinatory manner (Cheng et al 2006;Weng et al 2016) and are recognized by RNA-binding proteins (RBPs) in the cleavage and polyadenylation (PA) complex. The PA complex contains more than 20 proteins, some of which form subcomplexes (Shi and Manley 2015).…”

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confidence: 99%

Comparative analysis of alternative polyadenylation in S. cerevisiae and S. pombe

et al. 2017

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Alternative polyadenylation (APA) is a widespread mechanism that generates mRNA isoforms with distinct properties. Here we have systematically mapped and compared cleavage and polyadenylation sites (PASs) in two yeast species, and Although >80% of the mRNA genes in each species were found to display APA, showed greater 3' UTR size differences among APA isoforms than did PASs in different locations of gene are surrounded with distinct sequences in both species and are often associated with motifs involved in the Nrd1-Nab3-Sen1 termination pathway. In strong motifs surrounding distal PASs lead to higher abundances of long 3' UTR isoforms than short ones, a feature that is opposite in Differences in PAS placement between convergent genes lead to starkly different antisense transcript landscapes between budding and fission yeasts. In both species, short 3' UTR isoforms are more likely to be expressed when cells are growing in nutrient-rich media, although different gene groups are affected in each species. Significantly, 3' UTR shortening in coordinates with up-regulation of expression for genes involved in translation during cell proliferation. Using strains deficient for Pcf11 or Pab2, we show that reduced expression of 3'-end processing factors lengthens 3' UTR, with Pcf11 having a more potent effect than Pab2. Taken together, our data indicate that APA mechanisms in and are largely different: has many of the APA features of higher species, and Pab2 in has a different role in APA regulation than its mammalian homolog, PABPN1.

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“…Alternative polyadenylation of RNA is a posttranscriptional modification that plays an important role in gene expression, as it produces mRNAs that share the same coding region, but differ in their 3 0 UTRs. This process is highly tissue specific and results in the generation of alternative mRNA isoforms with different stability rates and translational efficiency and even subcellular localization [84][85][86]. In mammals, the poly(A) cleavage/polyadenylation site is composed of three sets of consensus cis-elements: the highly conserved AAUAAA hexamer and less conserved U/GU-rich and UGUA elements.…”

Section: Poly(a) Tail and Polyadenylation Sequencesmentioning

confidence: 99%

Mammalian Cis-Acting RNA Sequence Elements

Louis¹,

Sagarsky²

2018

Gene Expression and Regulation in Mammalian Cells - Transcription From General Aspects

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Cis-acting regulatory sequence elements are sequences contained in the 3 0 and 5 0 untranslated region, introns, or coding regions of precursor RNAs and mature mRNAs that are selectively recognized by a complementary set of one or more trans-acting factors to regulate posttranscriptional gene expression. This chapter focuses on mammalian cis-acting regulatory elements that had been recently discovered in different regions: pre-processed and mature. The chapter begins with an overview of two large networks of mRNAs that contain conserved AU-rich elements (AREs) or GU-rich elements (GREs), and their role in mammalian cell physiology. Other, less conserved, cisacting elements and their functional role in different steps of RNA maturation and metabolism will be discussed. The molecular characteristics of pathological cis-acting sequences that rose from gene mutations or transcriptional aberrations are briefly outlined, with the proposed approach to restore normal gene expression. Concise models of the function of posttranscriptional regulatory networks within different cellular compartments conclude this chapter.

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Poly(A) code analyses reveal key determinants for tissue-specific mRNA alternative polyadenylation

Cited by 19 publications

References 38 publications

Genetic Basis of Alternative Polyadenylation is an Emerging Molecular Phenotype for Human Traits and Diseases

Genetic Basis of Alternative Polyadenylation is an Emerging Molecular Phenotype for Human Traits and Diseases

Comparative analysis of alternative polyadenylation in S. cerevisiae and S. pombe

Mammalian Cis-Acting RNA Sequence Elements

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