The role of splicing factor PTBP1 in mechanotransduction
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ABSTRACT:
PROVIDER: PRJNA1172605 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30981177_1.fastq.gz | Fastqsanger.gz | |||
| SRR30981177_2.fastq.gz | Fastqsanger.gz | |||
| SRR30981178_1.fastq.gz | Fastqsanger.gz | |||
| SRR30981178_2.fastq.gz | Fastqsanger.gz | |||
| SRR30981179_1.fastq.gz | Fastqsanger.gz |
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Project description:Mechanical cues play a vital role in numerous biological processes, including embryonic development, aging, cellular homeostasis, and disease progression. Cells sense and convert these mechanical signals into biochemical responses that regulate cell behaviours like proliferation and migration through a process known as mechanotransduction. In this study, we present a comprehensive, large-scale approach to identify proteins with a mechanosensitive nuclear localisation and therefore a potential role in mechanotransduction. Our screening method is based on inducing acute changes in cellular traction forces, combined with in situ biotinylation of nuclear proteins, followed by mass spectrometry analysis. This screen approach identified among other proteins the splicing factor PTBP1 as a protein with mechanosensitive nuclear localisation, and we show that its nuclear abundance can be regulated by mechanical cues such as cell density, cell size, and extracellular matrix (ECM) stiffness. Moreover, we demonstrate that PTBP1 is essential for ECM stiffness-driven mesenchymal stem cell differentiation into osteoblasts, as well as for epithelial cell spreading and stiffness-induced proliferation. Furthermore, we show that PTBP1 mediates mechanosensitive alternative splicing of the endocytic adapter protein Numb, and that this splicing event affects the membrane trafficking of the mechanosensor integrin beta1 and is critical for matrix stiffness-induced stem cell differentiation and epithelial cell proliferation and cell spreading. Our findings support the emerging concept that alternative splicing plays a crucial role in mechanotransduction, offering new mechanistic insights into how matrix stiffness influences cellular mechanoresponses.
2025-03-30 | GSE279391 | GEO
Project description:Cells sense and respond to mechanical cues from their environment. Mechanical cues have been shown to be important for many biological processes, including embryonic development, aging, cellular homeostasis, and diseases. Cells translate mechanical cues into cellular biochemical signals that govern cellular behaviour like proliferation or migration, via a process called mechanotransduction. However this process and the proteins involved remain incompletely understood. Here, we present an unbiased and large scale screen approach to identify proteins involved in mechanotransduction. The screen revealed that the splicing factor PTBP1 is a novel mechanotransducer. We show that the nuclear localisation of PTBP1 depends on the extracellular matrix stiffness, cell density, and the actomyosin-based contractility of the cell. Furthermore, we demonstrate that PTBP1 promotes the mechanosensitive splicing of the adapter protein Numb, and that alternative splicing of Numb is crucial for matrix stiffness-induced proliferation. Our results support the idea that changes in alternative splicing are an integral part of mechanotransduction and provide a mechanism by which matrix stiffness regulates cell proliferation and the formation of a mechanomemory in cells.
2025-03-31 | PXD046157 | Pride
Project description:Changing splicing factors leads to abnormal alternative splicing (AS), which results in tumor progression.Splicing factor polypyrimidine tract binding proteins (PTBP1) facilitate cancer progression by modulating oncogenic variants. However, its role and mechanism in hepatocellular carcinoma (HCC) remains unclear. Our findings confirm that PTBP1 is highly expressed in HCC cells lines and tissues. Moreover, its expression correlated negatively with overallanddisease-freesurvivalrates, but inversely with tumor grade and stage. PTBP1 knockdown decreases HCC cell proliferation, migration, and invasion in vitro and inhibits hepatoma xenograft growth and infiltration in vivo. We identified PTBP1-mediated AS events and PTBP1 functionally promoted cell proliferation, invasion, and migration by altering the AS of the protein tau (MAPT) gene and promoting the oncogene expression. Strikingly, the dysregulation of MAPT splicing was paralleled by the increased expression of PTBP1 in HCC, which predicted the poor prognosis of the patients. According to additional research, AS of the MAPT gene guided by PTBP1 increases tumorigenicity in HCC by activating the MAPK/ERK pathways. In summary, our results suggest that PTBP1 plays an oncogenic role in HCC partially through the regulation of MAPT's AS, which could be a promising treatment target.
2025-04-30 | GSE250316 | GEO
Project description:We examined the role of PTBP1 in regulation of co-transcriptional splicing process by depleting this RNA-binding protein from embryonic stem cells using the auxin-inducible degron technology and analysing the total and chromatin-associated RNA fractions by RNA-seq. We also performed mNET-seq and ChIP-seq analyses using RNA polymerase II- and PTBP1-specific antibodies, respectively. Our data suggest that PTBP1 activates co-transcriptional splicing of hundreds of introns, a surprising effect given that PTBP1 is better known as a splicing repressor. Importantly, some co-transcriptionally activated introns fail to be spliced post-transcriptionally without PTBP1. In a striking example of this regulation, lasting retention of a PTBP1-dependent intron triggers nonsense-mediated decay of mRNAs encoding DNA methyltransferase DNMT3B, explaining their natural expression dynamics in development. Our further analyses suggest that this mechanism may protect differentiation-specific genes from aberrant methylation. We conclude that PTBP1-activated co-transcriptional splicing underlies biologically important decisions.
2023-01-08 | E-MTAB-11544 | biostudies-arrayexpress
Project description:RNA binding proteins play an important role in regulating alternative pre-mRNA splicing and in turn cellular gene expression. Polypyrimidine tract binding proteins, PTBP1 and PTBP2, are paralogous RNA binding proteins that play a critical role in the process of neuronal differentiation and maturation; changes in the concentration of PTBP proteins during neuronal development direct splicing changes in many transcripts that code for proteins critical for neuronal differentiation. How the two related proteins regulate different sets of neuronal exons is unclear. The distinct splicing activities of PTBP1 and PTBP2 can be recapitulated in an in vitro splicing system with the differentially regulated N1 exon of the c-src pre-mRNA. Here, we conducted experiments under these in vitro splicing conditions to identify PTBP1 and PTBP2 interacting partner proteins.
2022-01-20 | PXD029899 | Pride
Project description:Splicing factor PTBP1 promotes hepatocarcinogenesis via oncogenic splice-switching of MAPT
| PRJNA1053358 | ENA
Project description:Radiotherapy is a curative arsenal for prostate cancer (PCa), but radioresistance seriously compromises its effectiveness. Dysregulated RNA splicing factors are extensively involved in tumor progression. Nonetheless, the role of splicing factors in radioresistance remains largely unexplored in PCa. Here, we identified 23 splicing factors that are differentially expressed between PCa and adjacent normal tissues across multiple public PCa databases. Among those genes, polypyrimidine tract binding protein 1 (PTBP1) was significantly upregulated in PCa and was positively associated with advanced clinicopathological features and poor prognosis. Gain- and loss-of-function experiments demonstrated that PTBP1 markedly reinforced genomic DNA stability to desensitize PCa cells to irradiation in vitro and in vivo. Mechanistically, PTBP1 interacted with the HnRNP associated with lethal yellow protein homolog (RALY) and regulated exon 5 splicing of methyltransferase 3b (DNMT3B) from DNMT3B-S to DNMT3B-L. Furthermore, upregulation of DNMT3B-L induced promoter methylation of dual-specificity phosphatase-2 (DUSP2) and subsequently inhibited DUSP2 expression, thereby increasing radioresistance in PCa. Our findings highlight the role of splicing factors in inducing aberrant splicing events in response to radiotherapy and the potential role of PTBP1 and DNMT3B-L in reversing radioresistance in PCa.
2025-01-01 | GSE276977 | GEO
Project description:Analysis of effects of Ptbp1 deletion on RNA splicing and expression in aortic endothelial cells
2022-06-27 | GSE206849 | GEO
Project description:RNA-binding proteins (RBPs) bind at different positions of pre-mRNA molecules to promote or reduce the usage of a particular exon. Seeking to understand the working principle of these positional effects, we develop a capture RIC-seq (CRIC-seq) method to enrich specific RBP-associated in situ proximal RNA-RNA fragments for deep sequencing. We determine hnRNPA1-, SRSF1-, and PTBP1-associated proximal RNA-RNA contacts and regulatory mechanisms in HeLa cells. Unexpectedly, the 3D RNA map analysis shows that PTBP1-associated loops in individual introns preferentially promote cassette exon splicing by accelerating asymmetric intron removal, whereas the loops spanning across cassette exon primarily repress splicing. These “positional rules” can faithfully predict PTBP1-regulated splicing outcomes. We further demonstrate that cancer-related splicing quantitative trait loci can disrupt RNA loops by reducing PTBP1 binding on pre-mRNAs to cause aberrant splicing in tumors. Our study presents a powerful method for exploring the functions of RBP-associated RNA-RNA proximal contacts in gene regulation and disease.
2023-03-22 | GSE210581 | GEO
Project description:RNA-binding proteins (RBPs) bind at different positions of pre-mRNA molecules to promote or reduce the usage of a particular exon. Seeking to understand the working principle of these positional effects, we develop a capture RIC-seq (CRIC-seq) method to enrich specific RBP-associated in situ proximal RNA-RNA fragments for deep sequencing. We determine hnRNPA1-, SRSF1-, and PTBP1-associated proximal RNA-RNA contacts and regulatory mechanisms in HeLa cells. Unexpectedly, the 3D RNA map analysis shows that PTBP1-associated loops in individual introns preferentially promote cassette exon splicing by accelerating asymmetric intron removal, whereas the loops spanning across cassette exon primarily repress splicing. These “positional rules” can faithfully predict PTBP1-regulated splicing outcomes. We further demonstrate that cancer-related splicing quantitative trait loci can disrupt RNA loops by reducing PTBP1 binding on pre-mRNAs to cause aberrant splicing in tumors. Our study presents a powerful method for exploring the functions of RBP-associated RNA-RNA proximal contacts in gene regulation and disease.
2023-03-22 | GSE222817 | GEO