A Generalized dSpliceType Framework to Detect Differential Splicing and Differential Expression Events Using RNA-Seq

Zhu, Dongxiao; Deng, Nan; Bai, Changxin

doi:10.1109/tnb.2015.2388593

Cited by 15 publications

(5 citation statements)

References 29 publications

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“…RNA-Seq libraries were prepared using the SMARTer® Stranded Total RNA Sample Prep Kit (634873 Clontech). Sequencing reads were aligned using STAR 50 , transcripts quantified using DESeq2 51 and differential splicing analysed by dSpliceType 52 . Random subsampling analysis via RSeQC 53 showed that the read coverage approached saturation of identified splice junctions, meaning that, statistically, all known and many of the novel junctions would have likely been identified at the coverage level achieved for all samples (Fig.…”

Section: Methodsmentioning

confidence: 99%

Altered splicing and cytoplasmic levels of tRNA synthetases in SF3B1-mutant myelodysplastic syndromes as a therapeutic vulnerability

Liberante

Lappin

Barros

et al. 2019

Sci Rep

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Myelodysplastic syndromes (MDS) are haematopoietic malignancies that are characterised by a heterogeneous clinical course. In recent years, sequencing efforts have uncovered recurrent somatic mutations within RNA splicing factors, including SF3B1, SRSF2, U2AF1 and ZRSR2 . The most frequently mutated gene is SF3B1 , mutated in 17% of MDS patients. While SF3B1 mutations and their effects on splicing have been well characterised, much remains to be explored about their more far-reaching effects on cellular homeostasis. Given that mRNA splicing and nuclear export are coordinated processes, we hypothesised that SF3B1 mutation might also affect export of certain mRNAs and that this may represent a targetable pathway for the treatment of SF3B1 -mutant MDS. We used CRISPR/Cas9-genome editing to create isogenic cellular models. Comprehensive transcriptome and proteome profiling of these cells identified alterations in the splicing and export of components of the translational machinery, primarily tRNA synthetases, in response to the SF3B1 K700E mutation. While steady-state protein synthesis was unaffected, SF3B1 mutant cells were more sensitive to the clinically-relevant purine analogue, 8-azaguanine. In this study, we also demonstrated that 8-azaguanine affects splicing. Our results suggest that the simultaneous targeting of RNA metabolism and splicing by 8-azaguanine represents a therapeutic opportunity for SF3B1-mutant myelodysplastic syndromes.

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Section: Methodsmentioning

confidence: 99%

Altered splicing and cytoplasmic levels of tRNA synthetases in SF3B1-mutant myelodysplastic syndromes as a therapeutic vulnerability

Liberante

Lappin

Barros

et al. 2019

Sci Rep

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“…Regardless, there are several strategies that are commonly applied for differential splicing (DS) analyses. The more widelyused ones include a subgenic feature count-based method (e.g., DEXSeq [47], edgeR [48] and JunctionSeq [49]), or an event/junction-based method (e.g., dSpliceType [50], MAJIQ [51], and rMATS [52]). While the latter is able to more easily identify and classify types of alternative splicing changes, it suffers from less robust statistical power that is afforded by the former methodology [53].…”

Section: Ablation Of Tgsrs Tgclk and Tgprp4 Perturbs Alternative Splicingmentioning

confidence: 99%

Identification and characterisation of splicing regulators in Toxoplasma gondii

Lee

Seizova

McMillan

et al. 2021

Preprint

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The splicing of mRNA constitutes a major source of co- and post-transcriptional regulation in metazoans. In particular, members of the serine/arginine (SR) protein family are essential splicing factors that are implicated in the regulation of gene expression and RNA metabolism. However, very little is known about these proteins in apicomplexans, a phylum that includes some of the most important global parasites. In this study, we investigated the suite of three uncharacterised SR proteins in Toxoplasma gondii and show that all three are found localised to nuclear speckles. We show, by genetic ablation, that TgSR1 is particularly important for T. gondii growth. Using RNA-seq, we also characterised the global gene expression and splicing regulation of these proteins. We find that the SR proteins regulate several types of alternative splicing of distinct but overlapping subsets of transcripts, as well as impacting transcript abundance. Most of the alternative splicing events are non-productive intron retention events that do not appear to affect transcript abundance. The splicing sites of the impacted transcripts are enriched in characteristic SR binding motifs. We also identified and conditionally knocked down two putative kinases of SR proteins. The kinases are localised to nuclear speckles and are essential to parasite survival. Their perturbation resulted in widespread changes to splicing, but the affected transcripts did not mirror the patterns seen in knockouts of individual SRs, suggesting an absence of a simple relationship between SRs and these putative kinase regulators. Overall, this study reveals a complex system of splicing factors and kinases that post-transcriptionally regulate gene expression in T. gondii.

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“…The PCC between HACE1 and OPTN and corresponding P-values are 0.6059 and 0.0121, respectively. The OPTN and RAB25 have an opposite effect in the autophagy mechanism 52,86 . Based on the above mentioned information, we hypothesize the biological regulation mechanism as follows.…”

Section: Discussionmentioning

confidence: 98%

A Network-guided Association Mapping Approach from DNA Methylation to Disease

Lin

Huang

2019

Sci Rep

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Aberrant DNA methylation may contribute to development of cancer. However, understanding the associations between DNA methylation and cancer remains a challenge because of the complex mechanisms involved in the associations and insufficient sample sizes. The unprecedented wealth of DNA methylation, gene expression and disease status data give us a new opportunity to design machine learning methods to investigate the underlying associated mechanisms. In this paper, we propose a network-guided association mapping approach from DNA methylation to disease (NAMDD). Compared with existing methods, NAMDD finds methylation-disease path associations by integrating analysis of multiple data combined with a stability selection strategy, thereby mining more information in the datasets and improving the quality of resultant methylation sites. The experimental results on both synthetic and real ovarian cancer data show that NAMDD substantially outperforms former disease-related methylation site research methods (including NsRRR and PCLOGIT) under false positive control. Furthermore, we applied NAMDD to ovarian cancer data, identified significant path associations and provided hypothetical biological path associations to explain our findings.

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A Generalized dSpliceType Framework to Detect Differential Splicing and Differential Expression Events Using RNA-Seq

Cited by 15 publications

References 29 publications

Altered splicing and cytoplasmic levels of tRNA synthetases in SF3B1-mutant myelodysplastic syndromes as a therapeutic vulnerability

Altered splicing and cytoplasmic levels of tRNA synthetases in SF3B1-mutant myelodysplastic syndromes as a therapeutic vulnerability

Identification and characterisation of splicing regulators in Toxoplasma gondii

A Network-guided Association Mapping Approach from DNA Methylation to Disease

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