The association of Alu repeats with the generation of potential AU-rich elements (ARE) at 3' untranslated regions.

An, Hyeong Jun; Lee, Doheon; Lee, Kwang Hyung; Bhak, Jong

doi:10.1186/1471-2164-5-97

Cited by 33 publications

(25 citation statements)

References 41 publications

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“…The poly(T) sequence that exists in antisense Alu elements is the source of ~40% of identified 3′UTR AU-rich elements (AREs), which regulate mRNA half-life through the competitive binding of proteins that stabilize or destabilize the transcript (Fig. 3A) (45). Additionally, LINEs and SINEs can activate the function of microRNAs (miRNAs) by acting as promoters for miRNA synthesis or as miRNA-binding sites in target mRNAs (46, 47) (Fig.…”

Section: Regulation Of Rna Processingmentioning

confidence: 99%

Retrotransposons as regulators of gene expression

Elbarbary

Lucas

Maquat

2016

Science

355

302

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Transposable elements (TEs) are both a boon and a bane to eukaryotic organisms, depending on where they integrate into the genome and how their sequences function once integrated. We focus on two types of TEs: long interspersed elements (LINEs) and short interspersed elements (SINEs). LINEs and SINEs are retrotransposons; that is, they transpose via an RNA intermediate. We discuss how LINEs and SINEs have expanded in eukaryotic genomes and contribute to genome evolution. An emerging body of evidence indicates that LINEs and SINEs function to regulate gene expression by affecting chromatin structure, gene transcription, pre-mRNA processing, or aspects of mRNA metabolism. We also describe how adenosine-to-inosine editing influences SINE function and how ongoing retrotransposition is countered by the body’s defense mechanisms.

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Section: Regulation Of Rna Processingmentioning

confidence: 99%

Retrotransposons as regulators of gene expression

Elbarbary

Lucas

Maquat

2016

Science

355

302

View full text Add to dashboard Cite

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“…In this connection, previous studies proposed a role of 3’UTR-embedded Alus in regulating mRNA stability. While Wilson et al [40] demonstrated that Alus at 3’UTR increase mRNA half-life, An et al [86] suggested that 3’UTR Alus could generate AU-rich elements that destabilize certain mRNAs. Other authors pointed to Alu RNAs embedded in 3’UTRs as microRNA targets that might influence gene expression [41].…”

Section: Discussionmentioning

confidence: 99%

“…Our results indicate that the orientation of the Alus inside 3’UTRs relative to the gene sense might also have an effect in the genesis of PPs. The presence of antisense Alus, which are generators of AU-rich elements, or inverted Alus could modify the localization of the transcript in the cytoplasm [86, 89], maybe increasing the probability of binding the SRP9/14 proteins.…”

Section: Discussionmentioning

confidence: 99%

Novel Role of 3’UTR-Embedded Alu Elements as Facilitators of Processed Pseudogene Genesis and Host Gene Capture by Viral Genomes

2016

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Since the discovery of the high abundance of Alu elements in the human genome, the interest for the functional significance of these retrotransposons has been increasing. Primate Alu and rodent Alu-like elements are retrotransposed by a mechanism driven by the LINE1 (L1) encoded proteins, the same machinery that generates the L1 repeats, the processed pseudogenes (PPs), and other retroelements. Apart from free Alu RNAs, Alus are also transcribed and retrotranscribed as part of cellular gene transcripts, generally embedded inside 3’ untranslated regions (UTRs). Despite different proposed hypotheses, the functional implication of the presence of Alus inside 3’UTRs remains elusive. In this study we hypothesized that Alu elements in 3’UTRs could be involved in the genesis of PPs. By analyzing human genome data we discovered that the existence of 3’UTR-embedded Alu elements is overrepresented in genes source of PPs. In contrast, the presence of other retrotransposable elements in 3’UTRs does not show this PP linked overrepresentation. This research was extended to mouse and rat genomes and the results accordingly reveal overrepresentation of 3’UTR-embedded B1 (Alu-like) elements in PP parent genes. Interestingly, we also demonstrated that the overrepresentation of 3’UTR-embedded Alus is particularly significant in PP parent genes with low germline gene expression level. Finally, we provide data that support the hypothesis that the L1 machinery is also the system that herpesviruses, and possibly other large DNA viruses, use to capture host genes expressed in germline or somatic cells. Altogether our results suggest a novel role for Alu or Alu-like elements inside 3’UTRs as facilitators of the genesis of PPs, particularly in lowly expressed genes. Moreover, we propose that this L1-driven mechanism, aided by the presence of 3’UTR-embedded Alus, may also be exploited by DNA viruses to incorporate host genes to their viral genomes.

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“…Primate specific Alu retrotransposons, which occupy ~11% of the human genome, are major players in this process (1,7). These provide non-canonical transcription factor binding sites and other regulatory sites that govern epigenetic modifications as well as provide cryptic splice sites that lead to alternative splicing or differential mRNA stability (5,(8)(9)(10)(11)(12)(13)(14). Alu-derived exons exhibit lineage specificity with high transcript inclusion levels and have much higher rates of evolution (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

“…We have shown that transcript isoform dynamics i.e., the relative proportion of exonized versus non-exonized isoforms of a gene, could be modulated by these events in viral recovery and stress response (19,20). Besides, Alus provide substrates for other regulatory events such as gain of poly-A sites, AU-rich motifs and miRNA recognition elements (MREs) that can result in alternative polyadenylation, mRNA decay or translation stalling; and formation of specific secondary structures (9,(21)(22)(23)(24)(25). We have also reported that Alu-MREs can alter transcript isoform dynamics during stress response and some of these sites seem to be evolving in humans (20).In our earlier study on 3177 Alu-exonized genes, we reported the co-occurrence of cis Alu antisense and A-to-I editing at the level of single Alu exons in 319 genes.…”

mentioning

confidence: 99%

Origin of a novel CYP20A1 transcript isoform through multiple Alu exaptations creates a potential miRNA sponge

Bhattacharya

Jha

Singhal

et al. 2019

Preprint

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Background: Primate-specific Alus contribute to transcriptional novelties in conserved gene regulatory networks. Alu RNAs are present at elevated levels in stress conditions and consequently leads to transcript isoform specific functional role modulating the physiological outcome. One of the possible mechanisms could be Alu nucleated mRNA-miRNA interplay.Result: Using combination of bioinformatics and experiments, we report a transcript isoform of an orphan gene, CYP20A1 (CYP20A1_Alu-LT) through exaptation of 23 Alus in its 9kb 3'UTR. CYP20A1_Alu-LT, confirmed by 3'RACE, is an outlier in length and expressed in multiple cell lines. We demonstrate its presence in single nucleus RNA-seq of ~16000 human cortical neurons (including rosehip neurons). Its expression is restricted to the higher primates. Most strikingly, miRanda predicts ~4700 miRNA recognition elements (MREs; with threshold< -25kcal/mol) for ~1000 miRNAs, which have majorly originated within the 3'UTR-Alus post exaptation. We hypothesized that differential expression of this transcript could modulate mRNA-miRNA networks and tested it in primary human neurons where CYP20A1_Alu-LT is downregulated during heat shock response and upregulated upon HIV1-Tat treatment. CYP20A1_Alu-LT could possibly function as a miRNA sponge as it exhibits features of a sponge RNA such as cytosolic localization and ≥10 MREs for 140 miRNAs. Small RNA-seq revealed expression of nine miRNAs that can potentially be sponged by CYP20A1_Alu-LT in neurons. Additionally, CYP20A1_Alu-LT expression was positively correlated (low in heat shock and high in Tat) with 380 differentially expressed genes that contain cognate MREs for these nine miRNAs. This set is enriched in genes involved in neuronal development and hemostasis pathways. Conclusion:We demonstrate a potential role for CYP20A1_Alu-LT as miRNA sponge through preferential presence of MREs within Alus in a transcript isoform specific manner. This highlights a novel component of Alu-miRNA mediated transcriptional modulation leading to physiological homeostasis.Nearly 14% of the human transcriptome contain exonized Alus, predominantly in the principal isoforms of genes. Exonization is frequently reported in genes that have arisen de novo in primates, with most of the events in 3'UTRs (18,19). Such exonized Alus can increase the regulatory possibilities for a transcript, in a spatio-temporal manner, through antisense, miRNAs, A-to-I RNA editing, alternative splicing and enhancers. We have shown that transcript isoform dynamics i.e., the relative proportion of exonized versus non-exonized isoforms of a gene, could be modulated by these events in viral recovery and stress response (19,20). Besides, Alus provide substrates for other regulatory events such as gain of poly-A sites, AU-rich motifs and miRNA recognition elements (MREs) that can result in alternative polyadenylation, mRNA decay or translation stalling; and formation of specific secondary structures (9,(21)(22)(23)(24)(25). We have also reported that Alu-MREs can alter trans...

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The association of Alu repeats with the generation of potential AU-rich elements (ARE) at 3' untranslated regions.

Cited by 33 publications

References 41 publications

Retrotransposons as regulators of gene expression

Retrotransposons as regulators of gene expression

Novel Role of 3’UTR-Embedded Alu Elements as Facilitators of Processed Pseudogene Genesis and Host Gene Capture by Viral Genomes

Origin of a novel CYP20A1 transcript isoform through multiple Alu exaptations creates a potential miRNA sponge

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