Alternative 3’UTRs play a widespread role in translation-independent mRNA association with endoplasmic reticulum
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ABSTRACT:
PROVIDER: PRJNA684047 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13237602.fastq.gz | Fastqsanger.gz | |||
| SRR13237603.fastq.gz | Fastqsanger.gz | |||
| SRR13237604.fastq.gz | Fastqsanger.gz | |||
| SRR13237605.fastq.gz | Fastqsanger.gz | |||
| SRR13237606.fastq.gz | Fastqsanger.gz |
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Project description:Transcripts encoding membrane and secreted proteins are known to undergo translation on endoplasmic reticulum (ER). Translation-independent ER association (TiERA) has been reported for certain mRNAs, but the phenomenon is poorly understood. Here, using cell fractionation, polysome profiling, and 3’ end sequencing, we examine TiERA of poly(A)+ RNAs in mouse C2C12 myoblast cells. We identify transcript features that facilitate TiERA, including transcript size and GG and GC content. Consistent with the feature analysis, alternative polyadenylation (APA) isoforms differ substantially in TiERA, with long 3’UTR isoforms generally having a higher TiERA potential than short 3’UTR isoforms. Importantly, the widespread 3’UTR lengthening taking place in cell differentiation leads to greater transcript association with ER in differentiated myotubes, despite that the TiERA potential being generally maintained. In addition, we show that TiERA correlates negatively with mRNA stability, highlighting 3’UTR-mediated mRNA decay on ER. Together, our data indicate that sequence and size features impact ER association independent of translation, leading to distinct mRNA metabolism for different transcript groups, and APA can alter transcript stability and translation through isoform-specific ER association.
2021-07-20 | GSE162971 | GEO
Project description:Alternative 3’UTRs play a widespread role in mRNA association with the endomembrane system
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Project description:Transcripts encoding membrane and secreted proteins are known to associate with the endoplasmic reticulum (ER) through translation. Here, using cell fractionation, polysome profiling, and 3' end sequencing, we show that transcripts differ substantially in translation-independent ER association (TiERA). Genes in certain functional groups, such as cell signaling, tend to have significantly higher TiERA potentials than others, suggesting the importance of ER association for their mRNA metabolism, such as localized translation. The TiERA potential of a transcript is determined largely by size, sequence content, and RNA structures. Alternative polyadenylation (APA) isoforms can have distinct TiERA potentials because of changes in transcript features. The widespread 3' UTR lengthening in cell differentiation leads to greater transcript association with the ER, especially for genes that are capable of expressing very long 3' UTRs. Our data also indicate that TiERA is in dynamic competition with translation-dependent ER association, suggesting limited space on the ER for mRNA association.
| S-EPMC8501909 | biostudies-literature
Project description:Transcripts encoding membrane and secreted proteins are known to have translation on endoplasmic reticulum (ER) through the signal recognition particle (SRP)-mediated mechanism. Translation-independent association of mRNAs with ER has also been reported, but poorly understood. Here, using 3’ end sequencing, we examine transcripts associated with polysomes on ER in mouse C2C12 cells. We identify transcript features that facilitate translation-independent ER association, including CDS size, 3’UTR size, and GC content. Interestingly, transcripts encoding nuclear proteins tend to have a higher ER association potential than other transcripts, suggesting localized translation to facilitate nuclear import. We show long 3’UTR isoforms are generally more likely to be associated with ER than short isoforms. Consistently, global shortening of 3’UTRs by knocking down CFI-25 expression leads to substantial alternation of mRNA association with ER. While ER association potentials of transcripts undifferentiated myoblasts are similar to those in differentiated myotubes, 3’UTR lengthening in differentiation leads to more transcripts associated with ER in myotubes. Moreover, translation-independent ER association correlates with low mRNA stability, which is exacerbated in cells with oxidative stress. Together, our data indicate that sequence and structure features of mRNAs facilitate ER association and translation, potentially impacting localization dynamics of protein products, and cellular stress remodels membrane-associated transcripts through mRNA stability regulation.
2023-04-15 | GSE150607 | GEO
Project description:In eukaryotic cells, the spatial regulation of protein expression is frequently conferred through the coupling of mRNA localization and the local control of translation. mRNA localization to the endoplasmic reticulum (ER) is a prominent example of such regulation and serves a ubiquitous role in segregating the synthesis of secretory and integral membrane proteins to the ER. Recent genomic and biochemical studies have now expanded this view to suggest a role for the ER in global protein synthesis. We have utilized cell fractionation and ribosome profiling to obtain a genomic survey of the subcellular organization of mRNA translation and report that ribosomal loading of mRNAs, a proxy for mRNA translation, is biased to the ER. Notably, ER-associated mRNAs encoding both cytosolic and topogenic signal-encoding proteins display similar ribosome loading densities, suggesting that ER-associated ribosomes serve a global role in mRNA translation. We propose that the partitioning of mRNAs and their translation between the cytosol and ER compartments may represent a novel mechanism for the post-transcriptional regulation of gene expression. HEK293 cells were fractionated between the cytosol and endoplasmic reticulum. Within each fraction, ribosome footprints were generated and sequenced. In parallel, total mRNA was sequenced.
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Project description:In eukaryotes, up to one-third of cellular proteins are targeted to the endoplasmic reticulum, where they undergo folding, processing, sorting and trafficking to subsequent endomembrane compartments. Targeting to the endoplasmic reticulum has been shown to occur co-translationally by the signal recognition particle (SRP) pathway or post-translationally by the mammalian transmembrane recognition complex of 40 kDa (TRC40) and homologous yeast guided entry of tail-anchored proteins (GET) pathways. Despite the range of proteins that can be catered for by these two pathways, many proteins are still known to be independent of both SRP and GET, so there seems to be a critical need for an additional dedicated pathway for endoplasmic reticulum relay. We set out to uncover additional targeting proteins using unbiased high-content screening approaches. To this end, we performed a systematic visual screen using the yeast Saccharomyces cerevisiae, and uncovered three uncharacterized proteins whose loss affected targeting. We suggest that these proteins work together and demonstrate that they function in parallel with SRP and GET to target a broad range of substrates to the endoplasmic reticulum. The three proteins, which we name Snd1, Snd2 and Snd3 (for SRP-independent targeting), can synthetically compensate for the loss of both the SRP and GET pathways, and act as a backup targeting system. This explains why it has previously been difficult to demonstrate complete loss of targeting for some substrates. Our discovery thus puts in place an essential piece of the endoplasmic reticulum targeting puzzle, highlighting how the targeting apparatus of the eukaryotic cell is robust, interlinked and flexible.
2016-11-30 | GSE85686 | GEO
Project description:Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and often associated with progression from benign to invasive, metastatic stages. Mutations inactivate tumor suppression by p53 and endow the protein with novel gain-of-function (GOF) activities that actively promote tumor progression, metastasis and therapy resistance. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 (mutp53) target gene. A comprehensive pan-cancer analysis revealed a highly significant correlation between GOF p53 mutations and elevated expression of ENTPD5. Mechanistically, regulation of ENTPD5 by mutp53 is mediated by the histone H3 lysine 4 (H3K4) methyltransferase COMPASS complex. ENTPD5 has been shown to function in the endoplasmic reticulum as a UDPase to promote the N-glycosylation and folding of membrane proteins such as growth factor receptors and integrins. We show ENTPD5 to be a mediator of mutp53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals N-glycosylation in the endoplasmic reticulum as a novel mechanism underlying the progression of tumors with mutp53 that could provide new possibilities for treating cancers driven by GOF p53 mutations.
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