RNA-Seq Analysis Reveals Localization-Associated Alternative Splicing across 13 Cell Lines

Zeng, Chao; Hamada, Michiaki

doi:10.3390/genes11070820

Cited by 12 publications

(12 citation statements)

References 83 publications

(98 reference statements)

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“…In PDAC, we observed that oncogenes are enriched in the set of genes that undergo differential IR between clusters IR-1 and IR-2. These findings would be consistent with a model in which failure to remove introns in oncogenes in IR-2 results in intron-containing transcripts that are detained in the nucleus and accumulate, a finding consistent with previous studies 47 – 50 . This would result in lower functional levels of the encoded tumor-promoting onco-proteins in IR-2 (Fig.…”

Section: Discussionsupporting

confidence: 92%

“…For these 24 RBP genes, intron retention levels and gene expression levels were both higher in IR-2 compared to IR-1 [47][48][49] . This may reflect an increased contribution to gene expression of poorly spliced transcripts that accumulate in the nucleus in IR-2, as has been observed in other systems [47][48][49][50] . This buildup of IR-containing transcripts in the nucleus in IR-2 could lower the production of functional RBP proteins in the cytoplasm.…”

Section: Role Of Rbps In Differential Intron Retention Between Ir Clumentioning

confidence: 55%

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Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate of <8%. Unsupervised clustering of 76 PDAC patients based on intron retention (IR) events resulted in two clusters of tumors (IR-1 and IR-2). While gene expression-based clusters are not predictive of patient outcome in this cohort, the clusters we developed based on intron retention were associated with differences in progression-free interval. IR levels are lower and clinical outcome is worse in IR-1 compared with IR-2. Oncogenes were significantly enriched in the set of 262 differentially retained introns between the two IR clusters. Higher IR levels in IR-2 correlate with higher gene expression, consistent with detention of intron-containing transcripts in the nucleus in IR-2. Out of 258 genes encoding RNA-binding proteins (RBP) that were differentially expressed between IR-1 and IR-2, the motifs for seven RBPs were significantly enriched in the 262-intron set, and the expression of 25 RBPs were highly correlated with retention levels of 139 introns. Network analysis suggested that retention of introns in IR-2 could result from disruption of an RBP protein−protein interaction network previously linked to efficient intron removal. Finally, IR-based clusters developed for the majority of the 20 cancer types surveyed had two clusters with asymmetrical distributions of IR events like PDAC, with one cluster containing mostly intron loss events. Taken together, our findings suggest IR may be an important biomarker for subclassifying tumors.

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Section: Discussionsupporting

confidence: 92%

Section: Role Of Rbps In Differential Intron Retention Between Ir Clumentioning

confidence: 55%

Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma

et al. 2020

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“…The decision of whether an RNA is translated, modified, preserved, or degraded, is dictated by the intracellular location of the RNA, which in turn determines the biological function of the RNA [ 110 ]. Subcellular targeting can, therefore, have a significant influence on the regulatory and biochemical potential of the translated protein.…”

Section: Abiotic Stressmentioning

confidence: 99%

Stress-Induced Changes in Alternative Splicing Landscape in Rice: Functional Significance of Splice Isoforms in Stress Tolerance

Ganie

Reddy

2021

Biology

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Improvements in yield and quality of rice are crucial for global food security. However, global rice production is substantially hindered by various biotic and abiotic stresses. Making further improvements in rice yield is a major challenge to the rice research community, which can be accomplished through developing abiotic stress-resilient rice varieties and engineering durable agrochemical-independent pathogen resistance in high-yielding elite rice varieties. This, in turn, needs increased understanding of the mechanisms by which stresses affect rice growth and development. Alternative splicing (AS), a post-transcriptional gene regulatory mechanism, allows rapid changes in the transcriptome and can generate novel regulatory mechanisms to confer plasticity to plant growth and development. Mounting evidence indicates that AS has a prominent role in regulating rice growth and development under stress conditions. Several regulatory and structural genes and splicing factors of rice undergo different types of stress-induced AS events, and the functional significance of some of them in stress tolerance has been defined. Both rice and its pathogens use this complex regulatory mechanism to devise strategies against each other. This review covers the current understanding and evidence for the involvement of AS in biotic and abiotic stress-responsive genes, and its relevance to rice growth and development. Furthermore, we discuss implications of AS for the virulence of different rice pathogens and highlight the areas of further research and potential future avenues to develop climate-smart and disease-resistant rice varieties.

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“…This association to ribosomes indicates that JPX transcripts can exit the nucleus, which contrasts what has previously been reported. One possibility that would reconcile the mostly nuclear localization of JPX and other nuclear lncRNAs with ribosome binding lies upon the alternative splicing of RNAs, which often results in multiple isoforms with possibly diverse cellular localizations (Yoshimoto et al 2017;Zeng and Hamada 2020). Indeed, for some lncRNAs highlighted here, significant association to ribosomes of specific splice variants was found exclusively in VCaP ER , hinting at potential mechanisms of nuclear export or ribosome binding exclusive to these isoforms.…”

Section: Discussionmentioning

confidence: 90%

“…We next asked what drives a nuclear lncRNA, such as JPX, to be shuttled into the cytoplasm to be translated. One possibility resides in the production of alternative isoforms for these lncRNAs, for which the subcellular localization could be cytoplasmic, a process under increasing scrutiny for various RNAs (Zeng and Hamada 2020;Yoshimoto et al 2017), which could lead to the production of peptides. We found that some lncRNAs with high TE ratios such as JPX, LINC00467 and WARS_AS1, showed several events of alternative splicing in VCaP ER (Fig.…”

Section: Enz-resistance Is Linked To Aberrant Long Non-coding Rna Association To Ribosomesmentioning

confidence: 99%

Prostate cancer resistance leads to a global deregulation of translation factors and unconventional translation of long non-coding RNAs

Lelong

Adjibade

Joncas

et al. 2021

Preprint

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Emerging evidence associates translation factors and regulators to tumorigenesis. Recent advances in our ability to perform global translatome analyses indicate that our understanding of translational changes in cancer resistance is still limited. Here, we characterize global translational changes that occur during the acquisition of prostate cancer (PCa) drug resistance. We generated a patient derived xenograft (PDX) model created from PCa cells to recapitulate key features of resistant PCa progression. From an enzalutamide-sensitive patient derived cell line (VCaP), we generated a castration resistant cell line (VCaPCRPC) and an enzalutamide resistant cell line (VCaPER). We performed Total and polyribosome-bound RNA sequencing and mass spectroscopy from both VCaPCRPC and VCaPER to reveal their respective translatomes. We found that in drug-resistant cells, RNAs associated to ribosomes were enriched for nuclear RNA and DNA binding related biological processes, whereas RNAs that are less associated showed enrichment for processes such as cell membrane and cell-cell junction related biological processes. These results were corroborated by mass spectrometry and suggest that translation is indeed affected during drug resistance. Furthermore, our analysis revealed enrichment of long non-coding RNAs associated to ribosomes, which may suggest aberrant translation or translation of novel peptides that can be considered as new biomarkers. Our findings thus point towards novel therapeutic avenues that may target drug-resistant cells.

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RNA-Seq Analysis Reveals Localization-Associated Alternative Splicing across 13 Cell Lines

Cited by 12 publications

References 83 publications

Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma

Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma

Stress-Induced Changes in Alternative Splicing Landscape in Rice: Functional Significance of Splice Isoforms in Stress Tolerance

Prostate cancer resistance leads to a global deregulation of translation factors and unconventional translation of long non-coding RNAs

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