Human introns contain conserved tissue-specific cryptic poison exons

NAR Genomics and Bioinformatics, Год журнала: 2024, Номер 6(4)

Опубликована: Сен. 28, 2024

Eukaryotic cells express a large number of transcripts from single gene due to alternative splicing. Despite hundreds thousands splice isoforms being annotated in databases, it has been reported that the current exon catalogs remain incomplete. At same time, introns human protein-coding (PC) genes contain evolutionarily conserved elements with unknown function. Here, we explore possibility some them represent cryptic exons are expressed rare conditions. We identified group similar terms evolutionary conservation and RNA-seq read coverage Genotype-Tissue Expression dataset. Most were poison, i.e. generated an nonsense-mediated decay (NMD) isoform upon inclusion, many showed signs tissue-specific cancer-specific expression regulation. performed A549 cell line treated cycloheximide inactivate NMD confirmed using quantitative polymerase chain reaction seven eight tested are, indeed, expressed. This study shows PC poison exons, which reside intronic regions not fully insufficient representation libraries.

Язык: Английский

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Protein-protein interactions shape trans-regulatory impact of genetic variation on protein expression and complex traits

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 3, 2024

Abstract Most genetic variants influence complex traits by affecting gene regulation. Yet, despite comprehensive catalogs of molecular QTLs, linking trait-associated to biological functions remains difficult. In this study, we re-analyzed large maps protein QTLs (pQTLs) show that genes with trans -pQTLs but without cis are under strong selective constraints and highly enriched in GWAS loci. We found their targets interacting pairs, coding regions significantly at protein-protein interactions (PPI) interfaces. By leveraging existing PPI annotations for -pQTL mapping, identified 26,028 influencing 1,061 clusters. The PPIs colocalized 66% loci per trait on average 50 traits, helping many cases link cellular function. Finally, effects multiple autoimmune converge the same PPIs, pinpointing complexes signaling pathways promising therapeutic target potential.

Язык: Английский

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The conserved landscape of RNA modifications and transcript diversity across mammalian evolution

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 24, 2024

Gene expression programs underpin the development of shared phenotypes, yet importance transcript complexity in shaping mammalian evolution remains unclear. Here we present a comprehensive long-read direct RNA sequencing atlas full-length transcripts and their m6A modifications across six tissues (hippocampus, frontal cortex, cerebellum, testes, skeletal muscle, liver) five mammals (human, mouse, rat, dog, cow) non-mammalian out-group (chicken). Our analysis reveals that 29% genes have multiple mammalian-conserved alternative transcripts, with 31% these showing tissue-specific switching major isoforms. We uncover extensive conservation coordinated splicing events, primarily driven by mutually associated exon splicing, particularly neural cytoskeletal genes. At epitranscriptome level, find 14.2% are conserved mammals, 39% analysed containing modification. work provides unprecedented insight into epitranscriptome, highlighting potential roles phenotypic diversity providing valuable resource for understanding post-transcriptional regulation evolutionary time.

Язык: Английский

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Alternative Splicing Landscape in Mouse Skeletal Muscle and Adipose Tissue: Effects of Intermittent Fasting and Exercise

The Journal of Nutritional Biochemistry, Год журнала: 2024, Номер 137, С. 109837 - 109837

Опубликована: Дек. 25, 2024

Alternative splicing contributes to diversify the cellular protein landscape, but aberrant is implicated in many diseases. To which extent mis-splicing insulin resistance as causal defect of type 2 diabetes and whether this can be reversed by lifestyle interventions largely unknown. Therefore, RNA sequencing data from skeletal muscle adipose tissue diabetes-susceptible NZO mice treated with or without intermittent fasting healthy C57BL/6J subjected exercise were analyzed for alternative differences using Whippet rMATS. Diet triggered comparable levels changes, although profile appeared more flexible than that tissue, 72-114 differential events less 25 tissue. Splicing changes induced time-restricted feeding, alternate-day generally mild, a maximal percent spliced (PSI) difference 67%, indicating plays rather minor role lifestyle-induced adaptations mice. However, intron retention contributed regulation gene expression, influencing genes whose expression was directly linked phenotypic parameters (e.g. Eno2 Pan2). Alternate-day promoted skipping exon 7 Mlxipl (coding ChREBP), thereby affecting glucose sensing module carbohydrate-responsive transcription factor. Both training led known diabetes-related GWAS Abcc8, Ifnar2, Smarcad1), highlighting potential metabolic relevance these changes.

Язык: Английский

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Direct and indirect effects of spliceosome disruption compromise gene regulation by Nonsense-Mediated mRNA Decay

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 28, 2024

ABSTRACT Pre-mRNA splicing, carried out in the nucleus by a large ribonucleoprotein machine known as spliceosome, is functionally and physically coupled to mRNA surveillance pathway cytoplasm called nonsense mediated decay (NMD). The NMD monitors for premature translation termination signals, which can result from alternative relying on exon junction complex (EJC) deposited exon-exon junctions spliceosome. Recently, multiple genetic screens human cell lines have identified numerous spliceosome components putative factors. Using publicly available RNA-seq datasets K562 HepG2 cells depleted of 18 different components, we find that natural targeted isoforms are upregulated when members catalytic reduced. While some this increase could be due widespread pleiotropic effects dysfunction (e.g., reduced expression factors mis-splicing their mRNAs), identify AQR, SF3B1, SF3B4 CDC40 may more direct role NMD. We also test hypothesis increased production novel substrates overwhelm correlation between amount detected degree inhibition observed. Finally, similar transcriptome alterations substrate upregulation observed treated with inhibitors derived retinitis pigmentosa patients mutations PRPF8 PRPF31 . Overall, our results show regardless cause, disruption upregulates broad set targets, contribute cellular spliceosomopathies. AUTHOR SUMMARY During gene expression, removes extraneous non-coding sequences precursor RNAs produce messenger RNA (mRNA) contiguous code protein sequence. To guard against splicing errors interrupt coding sequence, linked In work, follow up recent findings several necessary efficient Our analysis transcriptomes lymphoblast based regulation compromised lacking proteins. Four these proteins effect even though general causes other changes indirectly affect suggest defective contributes spliceosomopathies, collection disorders caused

Язык: Английский

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Origins and Implications of Intron Retention Quantitative Trait Loci in Human Tissues

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 16, 2024

Abstract Intron retention is a type of alternative splicing in which introns remain unspliced mature RNA transcripts. In order to explore the landscape and consequences genetically regulated intron retention, we perform an quantitative trait loci (irQTL) analysis 49 human tissues across 838 individuals. We identify 8,624 unique events associated with genetic polymorphisms. 1,369 irQTLs (16%) are also genome-wide association study (GWAS) traits, suggesting that may play causal role regulation these GWAS traits. 1,999 (23%) colocalize eQTLs their respective gene, steady-state gene expression levels by shared sets variants. Through colocalization irQTL:eQTL events, demonstrate sufficient generate when one alternatively spliced transcripts preferentially targeted nonsense mediated decay (NMD) pathway. Surprisingly, for whose potential NMD effects can be confidently predicted based on positions within known annotations, find 58.8% (923/1570) colocalized irQTL eQTL pairs show effect size directions discordant model. Moreover, significantly more likely occur same direction as compared exon skipping QTLs. mathematical modeling experimental perturbation data, provide evidence able altering steady state ratios transcripts, postulate this mechanism partially underlie widespread observed previously various biological conditions. Taken together, results closely intertwined regulate phenotypic

Язык: Английский

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