Noncanonical Alternative Polyadenylation Contributes to Gene Regulation in Response to Hypoxia

Lorenzo, Laura de; Sorenson, Reed; Bailey‐Serres, Julia; Hunt, Arthur G.

doi:10.1105/tpc.16.00746

Cited by 75 publications

(85 citation statements)

References 92 publications

(135 reference statements)

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“…Here, we observe that it is 2.86 ± 0.10 times more likely to see a 5'-end in an intron that contains a 3'-end, and hence the enrichment of poly(A)-seq clusters within PCCRs also implies the enrichment of 5'-ends and CAGE clusters. These observations are, at least in part, physiological because U1 snRNP knockdown causes splicing inhibition and premature cleavage and polyadenylation in numerous introns near the start of the transcript [100], and there are multiple lines of evidence for the existence of PAS in 5'-UTR in plants [101,102].…”

Section: Discussionmentioning

confidence: 99%

Conserved long-range base pairings are associated with pre-mRNA processing of human genes

Kalmykova

Kalinina

Denisov

et al. 2020

Preprint

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The ability of nucleic acids to form double-stranded structures is essential for all living systems on Earth. While DNA employs it for genome replication, RNA molecules fold into complicated secondary and tertiary structures. Current knowledge on functional RNA structures in human protein-coding genes is focused on locally-occurring base pairs. However, chemical crosslinking and proximity ligation experiments have demonstrated that long-range RNA structures are highly abundant. Here, we present the most complete to-date catalog of conserved long-range RNA structures in the human transcriptome, which consists of 1.1 million pairs of conserved complementary regions (PCCRs). PCCRs tend to occur within introns proximally to splice sites, suppress intervening exons, circumscribe circular RNAs, and exert an obstructive effect on cryptic and inactive splice sites. The double-stranded structure of PCCRs is supported by a significant decrease of icSHAPE nucleotide accessibility, high abundance of A-to-I RNA editing sites, and frequent nearby occurrence of forked eCLIP peaks. Introns with PCCRs show a distinct splicing pattern in response to RNA Pol II slowdown suggesting that splicing is widely affected by co-transcriptional RNA folding. Additionally, transcript starts and ends are strongly enriched in regions between complementary parts of PCCRs, leading to an intriguing hypothesis that RNA folding coupled with splicing could mediate co-transcriptional suppression of premature cleavage and polyadenylation events. PCCR detection procedure is highly sensitive with respect to bona fide validated RNA structures at the expense of having a high false positive rate, which cannot be reduced without loss of sensitivity.The catalog of PCCRs is visualized through a UCSC Genome Browser track hub to facilitate further genome research on long-range RNA structures.Double-stranded structure is a key feature of nucleic acids that enables replicating the genomic information and underlies fundamental cellular processes [1,2]. Many RNAs adopt functional secondary structures, and mRNAs are no exception although their main role is to encode proteins [3,4,5,6]. In eukaryotes, RNA structure affects gene expression through modulating all steps of pre-mRNA processing including splicing [7], cleavage and polyadenylation [8], and RNA editing [9]. The loss of functional RNA structure has been increasingly reported as implicated in hereditary disease and cancer [10,11,12,13].Recent progress in high-throughput sequencing techniques enabled several experimental strategies to determine RNA structure in vivo [14,15,16]. Chemical RNA structure probing can reveal which bases are single-or double-stranded, but it cannot determine which nucleotides form base pairs [17,18,19,20,21].In order to identify the interacting partners, RNA structure probing has to be combined with de novo RNA structure prediction [22], but due to a number of technical limitations such methods cannot account for base pairings that are far apart [23]. Photo-inducible RNA crosslinking a...

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Section: Discussionmentioning

confidence: 99%

Conserved long-range base pairings are associated with pre-mRNA processing of human genes

Kalmykova

Kalinina

Denisov

et al. 2020

Preprint

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“…Similarly, FPA (an RNA‐binding protein of the spen gene family) controls APA of antisense FCA transcripts (Hornyik, Terzi, & Simpson, ); CstF‐64 and CstF‐77 are probably also involved in this mechanism (F. Liu, Marquardt, Lister, Swiezewski, & Dean, ). Recent high‐throughput studies in Arabidopsis, red clover ( Trifolium pratense L.), and rice have uncovered suggestive patterns in tissue‐specific APA in those species (Chakrabarti, Dinkins, & Hunt, ; de Lorenzo, Sorenson, Bailey‐Serres, & Hunt, ; Fu et al, ). Finally, we would remiss if not to mention the considerable research into polyadenylation mechanisms in Arabidopsis and other plants, which affect gene expression in embryo and gametophyte development, flowers, leaves, and other plant tissues (Hunt et al, ; Lorkovic, ; Xing, Zhao, & Li, ).…”

Section: Other Tissues Other Organismsmentioning

confidence: 99%

Tissue‐specific mechanisms of alternative polyadenylation: Testis, brain, and beyond (2018 update)

MacDonald

2019

WIREs RNA

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Alternative polyadenylation (APA) is how genes choose different sites for 3′ end formation for mRNAs during transcription. APA often occurs in a tissue‐ or developmental stage‐specific manner that can significantly affect gene activity by changing the protein product generated, the stability of the transcript, its localization within the cell, or its translatability. Despite the important regulatory effects that APA has on tissue‐specific gene expression, only a few examples have been characterized mechanistically. In this 2018 update to our 2010 review, we examine mechanisms for the control of APA and update our understanding of the older mechanisms since 2010. We once postulated the existence of tissue‐specific factors in APA. However, while a few tissue‐specific polyadenylation factors are known, the emerging conclusion is that the majority of APA is accomplished by altering levels of core polyadenylation proteins. Examples of those core proteins include CSTF2, CPSF1, and subunits of mammalian cleavage factor I. But despite support for these mechanisms, no one has yet documented any of these proteins changing in either a tissue‐specific or developmental manner. Given the profound effect that APA can have on gene expression and human health, improved understanding of tissue‐specific APA could lead to numerous advances in gene activity control. This article is categorized under: RNA Processing > 3′ End Processing RNA in Disease and Development > RNA in Development

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“…Differential selection of polyadenylation sites (alternative polyadenylation, APA) is used to generate new transcripts, and to improve the stability or capability of protein translation (Di Giammartino et al ., ; Lutz and Moreira, ; Akman and Erson‐Bensan, ). Genome‐wide studies in yeast, animals and plants have shown that a large proportion of genes have multiple poly(A) sites (Nagalakshmi et al ., ; Fu et al ., ; De Lorenzo et al ., ). Although the largest number of polyadenylation events occurs at the 3′ untranslated region (3′‐UTR), APA may also occur at different regions inside loci (5′‐UTRs, introns or exons), which are known as non‐canonical sites.…”

Section: Introductionmentioning

confidence: 97%

The polyadenylation factor FIP1 is important for plant development and root responses to abiotic stresses

et al. 2019

Self Cite

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Root development and its response to environmental changes is crucial for whole plant adaptation. These responses include changes in transcript levels. Here, we show that the alternative polyadenylation (APA) of mRNA is important for root development and responses. Mutations in FIP1, a component of polyadenylation machinery, affects plant development, cell division and elongation, and response to different abiotic stresses. Salt treatment increases the amount of poly(A) site usage within the coding region and 5 0 untranslated regions (5 0 -UTRs), and the lack of FIP1 activity reduces the poly(A) site usage within these non-canonical sites. Gene ontology analyses of transcripts displaying APA in response to salt show an enrichment in ABA signaling, and in the response to stresses such as salt or cadmium (Cd), among others. Root growth assays show that fip1-2 is more tolerant to salt but is hypersensitive to ABA or Cd. Our data indicate that FIP1-mediated alternative polyadenylation is important for plant development and stress responses.

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Noncanonical Alternative Polyadenylation Contributes to Gene Regulation in Response to Hypoxia

Cited by 75 publications

References 92 publications

Conserved long-range base pairings are associated with pre-mRNA processing of human genes

Conserved long-range base pairings are associated with pre-mRNA processing of human genes

Tissue‐specific mechanisms of alternative polyadenylation: Testis, brain, and beyond (2018 update)

The polyadenylation factor FIP1 is important for plant development and root responses to abiotic stresses

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