Neuron type-specific mRNA translation programs provide a gateway for memory consolidation.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Summary Long-term memory consolidation is a dynamic process that requires heterogeneous ensemble of neurons, each with highly specialized molecular environment. Considerable effort has been placed into understanding how the mechanisms in specific neuron types are modified memory, but these studies often undertaken hours or days after training, when already consolidated. Studies have shown protein synthesis elevated during early stages consolidation, there limited information as to it impacts neuronal function. We hypothesize mRNAs being translated could provide clues diverse neurons involved formation restructure their architecture support formation. Here, we generate landscape translatome three dorsal hippocampus first hour contextual consolidation. Our results show share common backbone readily mRNAs. However, excitatory undergo deep reconfiguration proteostatic control, whereas interneurons modify synaptic transmission. demonstrate translational control GADD34, which promotes translation initiation. Finally, differential expression by can be explained features hard coded mRNA, suggesting ubiquitous controlling activity-dependent translation. Altogether, our work uncovers previously unknown checkpoints and provides large, available resource for further investigations health disease.

Language: Английский

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An ultra-conserved poison exon in the Tra2b gene encoding a splicing activator is essential for male fertility and meiotic cell division

The EMBO Journal, Journal Year: 2025, Volume and Issue: 44(3), P. 877 - 902

Published: Jan. 2, 2025

The cellular concentrations of splicing factors (SFs) are critical for controlling alternative splicing. Most serine and arginine-enriched (SR) protein SFs regulate their own concentration via a homeostatic feedback mechanism that involves regulation inclusion non-coding 'poison exons' (PEs) target transcripts nonsense-mediated decay. importance SR PE during animal development is largely unknown despite ultra-conservation across genomes. To address this, we used mouse genetics to disrupt an ultra-conserved in the Tra2b gene encoding Tra2β. Focussing on germ cell development, found deletion causes azoospermia due catastrophic death meiotic prophase. Failure proceed through meiosis was associated with increased expression sufficient drive aberrant Tra2β hyper-responsive splice patterns. Although prophase, spared earlier mitotically active cells, even though these still required function. Our data indicate control prevents accumulation toxic levels incompatible This unexpected connection male fertility helps explain indicates evaluating function models.

Language: Английский

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Specifying cellular context of transcription factor regulons for exploring context-specific gene regulation programs

NAR Genomics and Bioinformatics, Journal Year: 2025, Volume and Issue: 7(1)

Published: Jan. 7, 2025

Abstract Understanding the role of transcription and factors (TFs) in cellular identity disease, such as cancer, is essential. However, comprehensive data resources for cell line-specific TF-to-target gene annotations are currently limited. To address this, we employed a straightforward method to define regulons that capture cell-specific aspects TF binding transcript expression levels. By integrating transcriptome data, generated 40 common lines comprising both proximal distal regulatory events. Through systematic benchmarking involving knockout experiments, demonstrated performance on par with state-of-the-art methods, our being easily applicable other types interest. We present case studies using three cancer single-cell datasets showcase utility these cell-type-specific exploring transcriptional dysregulation. In summary, this study provides valuable pipeline resource systematically regulations, emphasizing network analysis deciphering disease mechanisms.

Language: Английский

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Poison exons: tuning RNA splicing for targeted gene regulation

Trends in Pharmacological Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Shiba: a versatile computational method for systematic identification of differential RNA splicing across platforms

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(4)

Published: Feb. 8, 2025

Abstract Alternative pre-mRNA splicing (AS) is a fundamental regulatory process that generates transcript diversity and cell type variation. We developed Shiba, comprehensive method integrates assembly, event identification, read counting, differential analysis across RNA-seq platforms. Shiba excels in capturing annotated unannotated AS events with superior accuracy, sensitivity, reproducibility. It addresses the often-overlooked issue of junction imbalance, significantly reducing false positives to aid target prioritization downstream analyses. Unlike other tools require large numbers biological replicates or resulting low sensitivity high positives, Shiba's statistics framework agnostic sample size, as demonstrated by simulated data its effective application real n= 1 datasets. To extend utility single-cell RNA-seq, we scShiba, which applies pseudobulk approach analyze at cluster level. scShiba successfully revealed regulation developmental dopaminergic neurons differences between excitatory inhibitory neurons. Both are available Docker/Singularity containers Snakemake pipelines, ensuring With their capabilities, enable systematic quantification alternative various platforms, laying solid foundation for mechanistic exploration functional complexity RNA splicing.

Language: Английский

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Establishment of an alternative splicing prognostic risk model and identification of FN1 as a potential biomarker in glioblastoma multiforme

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 25, 2025

Aberrant alternative splicing and abnormal events (ASEs) in glioblastoma multiforme (GBM) remain largely elusive. The prognostic-associated ASEs GBM were identified summarized into 123 genes using LGG datasets from ASCancer Atlas TCGA. eleven (C2, COL3A1, CTSL, EIF3L, FKBP9, FN1, HPCAL1, HSPB1, IGFBP4, MANBA, PRKAR1B) screened to develop an prognostic risk score (ASRS) model through machine learning algorithms. was trained on the TCGA-GBM cohort validated with four external CGGA GEO, achieving AUC values of 0.808, 0.814, 0.763, 0.859, 0.836 for 3-year survival rates, respectively. ASRS could be independent factor patients (HR > 1.8 across three datasets) multivariate Cox regression analysis. high-risk group demonstrated poorer prognosis, elevated immune scores, increased levels cell infiltration, greater differences drug sensitivity. We found that used construction, contained 4 resulting high expression non-canonical transcripts presence premature termination codon. These may regulated by tumour-related factors according PPI network. Furthermore, both mRNA protein FN1 highly expressed compared LGG, correlating poor prognosis GBM. In conclusion, our findings highlight role affecting progression GBM, showed a potential application patients. serve as promising biomarker mechanisms processes aberrant need revealed future.

Language: Английский

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Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing

Nature Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Language: Английский

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Coupling mechanisms coordinating mRNA translation with stages of the mRNA lifecycle

RNA Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 21, 2025

Gene expression involves a series of consequential processes, beginning with mRNA synthesis and culminating in translation. Traditionally studied as linear sequence events, recent findings challenge this perspective, revealing coupling mechanisms that coordinate key steps gene expression, even when spatially temporally distant. In review, we focus on translation, the final stage examine its stages metabolism: synthesis, processing, export, decay. For each these provide an overview known instances Furthermore, discuss role high-throughput technologies uncovering intricate interactions genome-wide scale. Finally, highlight challenges propose future directions to advance our understanding how orchestrate robust adaptable programs.

Language: Английский

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Impact of disease-associated chromatin accessibility QTLs across immune cell types and contexts

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 12, 2024

Abstract Only a third of immune-associated loci from genome-wide association studies (GWAS) colocalize with expression quantitative trait (eQTLs). To learn about causal genes and mechanisms at the remaining loci, we created unified single-cell chromatin accessibility (scATAC-seq) map in peripheral blood comprising total 282,424 cells 48 individuals. Clustering topic modeling scATAC data identified discrete cell-types continuous cell states, which helped reveal disease-relevant cellular contexts, allowed mapping genetic effects on across these contexts. We 37,390 QTLs (caQTL) 10% FDR eight groups observed extensive sharing caQTLs immune finding that fewer than 20% are specific to single type. Notably, colocalized ∼50% more GWAS compared eQTLs, helping nominate putative for many unexplained loci. However, most GWAS-caQTL colocalizations had no detectable downstream regulatory gene levels same find evidence higher rates colocalization between signals reflect missing contexts among existing eQTL studies. Thus, there remains pressing need identifying disease-causing variation cells.

Language: Английский

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Multimodal analysis of RNA sequencing data powers discovery of complex trait genetics

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 29, 2024

Abstract RNA sequencing has the potential to reveal many modalities of transcriptional regulation, such as various splicing phenotypes, but studies on gene regulation are often limited expression due complexity extracting and analyzing multiple phenotypes. Here, we present Pantry, a framework efficiently generate diverse phenotypes from data perform downstream integrative analyses with genetic data. Pantry generates six (gene expression, isoform ratios, splice junction usage, alternative TSS/polyA stability) integrates them via QTL mapping, TWAS, colocalization testing. We apply Geuvadis GTEx data, finding that 4768 genes no identified eQTL in have at least one other modality, resulting 66% increase over mapping. further found exhibit modality-specific functional properties reinforced by joint analysis different modalities. also show generalizing TWAS approximately doubles discovery unique gene-trait associations, enhances identification regulatory mechanisms underlying GWAS signal 42% previously associated pairs.

Language: Английский

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