mRNA 3′-UTR shortening is a molecular signature of mTORC1 activation

Chang, Ju Young; Zhang, Wei; Yeh, Hsin Sung; Jong, Ebbing P. de; Jun, Semo; Kim, Kwan Hyun; Bae, Sun Sik; Beckman, Kenneth B.; Hwang, Tae Hyun; Kim, Kye Seong; Kim, Do-Hyung; Griffin, Timothy J.; Kuang, Rui; Yong, Jeongsik

doi:10.1038/ncomms8218

Cited by 60 publications

(66 citation statements)

References 47 publications

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“…The length of the 3' UTR, and in particular the use of APA sites, is implicated in a number of pathologies including cancer and cell senescence, and in cellular stress response (Chang et al, 2015;Chen et al, 2018a;Mayr and Bartel, 2009). Senescence of cultured primary cells, for example, is a phenomenon linked to NL biology and to the reduction of lamin-B1 (Freund et al, 2014;Shimi et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

The versatility of Ascorbate Peroxidase-aided mapping uncovers insights of the nuclear lamina interactions and function

Tran

Paulson

Moresco

et al. 2020

Preprint

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The nuclear lamina (NL) is a proteinaceous network found beneath the inner nuclear membrane. The NL is linked to a number of dynamic cellular activities including chromatin organization, transcription and RNA/protein trafficking through nuclear pores. Our understanding of the NL has been hindered in part by the general insolubility and low extractability of proteins from this region. This has spurred the development of proximity ligation methods that label proteins and/or DNA near the NL for systematic identification (Bar et al., 2018; Chen et al., 2018b; Guelen et al., 2008; Roux et al., 2012). To simplify labeling and improve temporal resolution, we fused APEX2 (Hung et al., 2014; Lam et al., 2015) to the nuclear lamina protein lamin-B1 to map proteins, RNA and DNA associated with the NL. We show that APEX2 labeling of the NL is robust and requires as little as 20 seconds. In addition to identifying the NL proteome, this method revealed NL-proximal RNA species that were largely spliced. These NL-proximal RNAs show a bias toward long 3’ UTRs, suggesting an RNA-regulatory role of the NL. This is further supported by the finding of a bias toward longer 3’ UTRs in genes deregulated in lamin-null cells. Interestingly, these RNAs share a sequence motif in their 3’ UTRs. Finally, we demonstrate that the APEX2 method can reliably map lamina-associated domains (LADs) at different stages of the cell cycle, revealing a variability of short LADs regions enriched for histone lysine 27 trimethylation (H3K27me3). Thus the APEX2 method report here is a useful addition to the molecular toolbox for the study of the NL and permits the identification of proteome, transcriptome, and genome elements associated with this nuclear substructure.

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Section: Discussionmentioning

confidence: 99%

The versatility of Ascorbate Peroxidase-aided mapping uncovers insights of the nuclear lamina interactions and function

Tran

Paulson

Moresco

et al. 2020

Preprint

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“…For example, isoforms using the proximal PAS, which encode truncated proteins or have short 3′ UTRs, are generally upregulated when neuronal cells are activated by membrane depolarization agents 177 , and activation of the mTOR pathway leads to global 3′ UTR shortening 178 . Although the mechanism underlying this APA is unknown, isoforms with shortened 3′ UTRs have greater translational potential as analysed by polysome profiling.…”

Section: Figurementioning

confidence: 99%

Alternative polyadenylation of mRNA precursors

Tian

Manley

2016

Nat Rev Mol Cell Biol

838

900

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Alternative polyadenylation (APA) is an RNA-processing mechanism that generates distinct 3′ termini on mRNAs and other RNA polymerase II transcripts. It is widespread across all eukaryotic species and is recognized as a major mechanism of gene regulation. APA exhibits tissue specificity and is important for cell proliferation and differentiation. In this Review, we discuss the roles of APA in diverse cellular processes, including mRNA metabolism, protein diversification and protein localization, and more generally in gene regulation. We also discuss the molecular mechanisms underlying APA, such as variation in the concentration of core processing factors and RNA-binding proteins, as well as transcription-based regulation.

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“…The APA profiles in different tissues are well conserved across species (Derti et al 2012) and ubiquitously expressed genes are more likely to have APA isoforms than those genes with restricted expression breadth (Lianoglou et al 2013). APA has also been shown to be dynamically regulated in cell proliferation , differentiation (Ji and Tian 2009;Shepard et al 2011), cancer transformation (Mayr and Bartel 2009;Singh et al 2009;Fu et al 2011;Morris et al 2012), and in response to extracellular cues (Flavell et al 2008;Chang et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Transcription elongation rate has a tissue-specific impact on alternative cleavage and polyadenylation in Drosophila melanogaster

Liu

Freitas

Zheng

et al. 2017

RNA

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Alternative polyadenylation (APA) is a mechanism that generates multiple mRNA isoforms with different 3'UTRs and/or coding sequences from a single gene. Here, using 3' region extraction and deep sequencing (3'READS), we have systematically mapped cleavage and polyadenylation sites (PASs) in , expanding the total repertoire of PASs previously identified for the species, especially those located in A-rich genomic sequences.-element analysis revealed distinct sequence motifs around fly PASs when compared to mammalian ones, including the greater enrichment of upstream UAUA elements and the less prominent presence of downstream UGUG elements. We found that over 75% of mRNA genes in undergo APA. The head tissue tends to use distal PASs when compared to the body, leading to preferential expression of APA isoforms with long 3'UTRs as well as with distal terminal exons. The distance between the APA sites and intron location of PAS are important parameters for APA difference between body and head, suggesting distinct PAS selection contexts. APA analysis of the mutant strain, which harbors a mutant RNA polymerase II (RNAPII) with a slower elongation rate, revealed that a 50% decrease in transcriptional elongation rate leads to a mild trend of more usage of proximal, weaker PASs, both in 3'UTRs and in introns, consistent with the "first come, first served" model of APA regulation. However, this trend was not observed in the head, suggesting a different regulatory context in neuronal cells. Together, our data expand the PAS collection for and reveal a tissue-specific effect of APA regulation by RNAPII elongation rate.

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mRNA 3′-UTR shortening is a molecular signature of mTORC1 activation

Cited by 60 publications

References 47 publications

The versatility of Ascorbate Peroxidase-aided mapping uncovers insights of the nuclear lamina interactions and function

The versatility of Ascorbate Peroxidase-aided mapping uncovers insights of the nuclear lamina interactions and function

Alternative polyadenylation of mRNA precursors

Transcription elongation rate has a tissue-specific impact on alternative cleavage and polyadenylation in Drosophila melanogaster

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