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Machine Learning Analysis of Circulating Alternative Spliced RNAs Reveal Segregation of Retained Intron Species with New-onset Type 1 Diabetes

ABSTRACT: Distinct patterns of RNA splicing differentiated participants with T1D from healthy unaffected controls. Notably, certain splicing events, particularly involving retained introns, showed significant association with T1D. Machine learning analysis using these splicing events as features from the training cohort demonstrated high accuracy in distinguishing between T1D subjects and controls in the validation cohort. Gene Ontology pathway enrichment analysis of the retained intron category showed evidence for a systemic viral response in T1D subjects.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277133 | GEO | 2024/09/18

REPOSITORIES: GEO

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Genome-wide identification of mis-spliced/intron-retained transcripts in Arabidopsis thaliana rcf1-1 mutant plants under cold stress as determined by tiling array analysis.

2013-02-25 | GSE41378 | GEO

Genome-wide identification of mis-spliced/intron-retained transcripts in Arabidopsis thaliana rcf1-1 mutant plants under normal growth conditions as determined by tiling array analysis.

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Genome-wide identification of mis-spliced/intron-retained transcripts in Arabidopsis thaliana rcf1-1 mutant plants under cold stress as determined by tiling array analysis.

Project description:Cold stress is one of the most severe environmental conditions which cause huge losses in crop production worldwide. We identified a DEAD box RNA helicase, RCF1 (Regulator of CBF gene expression 1) that controls pre-mRNA splicing of cold-stress-responsive genes including positive and negative regulators of CBF genes. We used whole genome tiling array analysis under cold stress to identify transcripts which are mis-spliced/intron-retained in rcf1-1. Fourteen-day-old wild type and rcf1-1 seedlings grown on MS agar medium (1x MS salts, 2% sucrose, 0.6% agar, pH 5.7) were subjected to cold stress at 4M-BM-0C for 12 h. Total RNA was extracted with Trizol reagent (Invitrogen) and synthesized into double-stranded DNA that was hybridized to whole genome tiling arrays (Affymetrix Arabidopsis Tiling1.0R). All hybridizations were performed with 3 biological replicates.

2013-02-25 | E-GEOD-41378 | biostudies-arrayexpress

Genome-wide identification of mis-spliced/intron-retained transcripts in Arabidopsis thaliana rcf1-1 mutant plants under normal growth conditions as determined by tiling array analysis.

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2013-02-25 | E-GEOD-41377 | biostudies-arrayexpress

Light regulates nuclear detainment of intron-retained transcripts through COP1-spliceosome to modulate photomorphogenesis

Project description:Intron retention (IR) is the most common alternative splicing (AS) event in Arabidopsis. Increasing studies have demonstrated a major role of IR in gene expression regulation. The impacts of IR on plant growth and development, and response to environments remains under explored. Here, we found that IR functions directly in gene expression regulation on a genome-wide scale through detainment of the intron-retained transcripts (IRTs) in the nucleus. Through this mechanism, nuclear-retained IRTs can be kept away from translation. COP1-dependent light modulation of IRTs of light signaling genes, such as PIF4, RVE1, and ABA3, contribute to seedling morphological development in responding to changing light conditions. Further, light-induced IR changes are under the control of the spliceosome, and in part through COP1-dependent ubiquitination and degradation of DCS1, a plant-specific spliceosomal component. Our data suggests that light regulates the activity of the spliceosome and the consequent IRTs nucleus detainment to modulate photomorphogenesis through COP1.

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Machine Learning Analysis of Circulating Alternative Spliced RNAs Reveal Segregation of Retained Intron Species with New-onset Type 1 Diabetes

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Genome-wide analysis of PTBP1-regulated retained introns in mESCs

Project description:Intron retention (IR) is an alternative splicing event where mRNAs containing unspliced introns are exported to the cytoplasm and then either translated, giving rise to new protein isoforms, or degraded via the nonsense-mediated decay pathway. However, unspliced introns are also seen in nuclear RNA. Some of these are spliced at a low rate but do eventually become fully spliced and their respective mRNAs exported, while others stay retained and are recognized by nuclear decay machineries. IR has been shown to be regulated during granulocyte and neuronal differentiation and in some cancers, and a subset of the nuclear retained introns, called detained introns, have been implicated in growth control pathways. Despite many findings on IR and its biological significance, it is still not clear whether an incompletely spliced intron observed is a true retained intron that is exported as an mRNA or is a product of slow splicing that remains in the nucleus. A better understanding is needed of the molecular events that reduce intron excision rate and determine the release of an RNA for export. We have found that some genes in mouse embryonic stem cells (mESCs) produce RNAs that are highly associated with the high molecular-weight nuclear pellet (chromatin), rather than the soluble nucleoplasm or cytoplasm. This chromatin-associated RNA is polyadenylated, usually contains one or more incompletely spliced introns, and is often extensively bound by polypyrimidine tract-binding protein 1 (PTBP1). We hypothesize that PTBP1 inhibits splicing of these introns, and this causes sequestration of the transcript on chromatin. We are studying the role of PTBP1 in inhibiting intron excision and anchoring RNAs in the nuclear and chromatin compartments of mESCs.

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The Impact of Pro-Inflammatory Cytokines on Alternative Splicing Patterns in Human Islets

Project description:Alternative splicing (AS) within the β cell has been proposed as one potential pathway that may exacerbate autoimmunity and unveil novel immunogenic epitopes in type 1 diabetes (T1D). We employed a computational strategy to prioritize pathogenic splicing events in human islets treated with IL-1β + IFN-γ as an ex vivo model of T1D and coupled this analysis with a k-mer based approach to predict RNA binding proteins involved in AS events. In total, 969 AS events were identified in cytokine-treated islets, with the majority (44.8%) involving a skipped exon. AS events occurred with high frequency in MHC Class II-related mRNAs, and targeted qPCR validated reduced inclusion of Exon5 in the MHC Class II gene HLA-DMB, while RNA FISH confirmed HLA-DMB splicing in pancreatic sections from human T1D donors. Together, these data suggest that dynamic control of AS plays a role in the β cell response to inflammatory signals during T1D evolution.

2022-12-16 | GSE169221 | GEO

DNA methylation regulates intron retention via altered MeCP2-mediated splicing factor recruitment

Project description:While intron retention (IR) is now recognized as a widespread and conserved mechanism of gene expression control, its regulation is poorly understood. Here, we identify significantly reduced DNA methylation levels near splice junctions flanking retained introns compared to non-retained introns in diverse primary cells and cell lines. Further, we identify increased IR following inhibition of DNA methylation indicating that reduced DNA methylation promotes IR. We demonstrate reduced occupancy of MeCP2 near the splice junctions of retained introns, mirroring the reduced DNA methylation at these sites. Accordingly, MeCP2 depletion in tissues/cells enhances IR. By analyzing the MeCP2 interactome, we demonstrate that decreased MeCP2 binding near splice junctions facilitates IR via reduced recruitment of the splicing factor, Tra2b, and increased RNA polymerase II stalling. Our study identifies a dynamic interplay between DNA methylation, MeCP2 and splicing factors including Tra2b in IR regulation and provides novel insights into the mechanisms governing splicing.

2017-02-28 | GSE85517 | GEO

RNA-Seq to evaluate detaining intron splicing upon O-GlcNAc perturbation

Project description:We report the effect of splicing upon O-GlcNAc perturbation with OGT inhibitor or OGA inhibitor. We found that splicing is acutely affected through our phosphoproteomics data when cells are treated with OGT inhibitor. By obtaining the various splicing events that are affected by OGT or OGA inhibition, we found that O-GlcNAc is a major regulator of detained introns splicing. At early time point, we observed highly specific splicing of OGT/OGA detained introns to buffer O-GlcNAc changes. At longer time point, ~80% of the total detained introns are affected by O-GlcNAc perturbation, while the rest of canonical splicing events are only minimally affected (~ 5%).

2020-04-03 | GSE138783 | GEO

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