Regulation of co-transcriptional splicing by RNA-binding protein PTBP1
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB51671 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR9286210_1.fastq.gz | Fastqsanger.gz | |||
| ERR9286210_2.fastq.gz | Fastqsanger.gz | |||
| ERR9286220_1.fastq.gz | Fastqsanger.gz | |||
| ERR9286220_2.fastq.gz | Fastqsanger.gz | |||
| ERR9286211_1.fastq.gz | Fastqsanger.gz |
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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: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 | GSE222816 | 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 | GSE210582 | 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
Project description:Analysis of effects of Ptbp1 deletion on RNA splicing and expression in aortic endothelial cells
2022-06-27 | GSE206849 | GEO
Project description:Ribosomopathies constitute a range of disabling conditions associated with defective protein synthesis mainly affecting hematopoietic stem cells (HSCs) and erythroid development. Here we demonstrate that deletion of Polypyrimidine Tract Binding Protein 1 (PTBP1) in the hematopoietic compartment led to the development of a ribosomopathy-like condition. Specifically, loss of PTBP1 was associated with a decrease in HSC self-renewal, erythroid differentiation and protein synthesis. Consistent with its function as a splicing regulator, PTBP1 deficiency led to splicing defects in hundreds of genes and we demonstrate that the up-regulation of a specific isoform of CDC42 could partly mimic the protein synthesis defect associated with loss of PTBP1. Furthermore, PTBP1 deficiency was associated with a marked defect in ribosome biogenesis and a selective reduction in the translation of mRNAs encoding ribosomal proteins. Collectively, this work identifies PTBP1 as a key integrator of ribosomal functions and highlights the broad functional repertoire of RNA binding proteins.
2022-05-04 | PXD023879 | Pride
Project description:Antibody affinity maturation occurs in germinal centres (GC) where B cells cycle between the light zone (LZ) and the dark zone. In the LZ GC B cells bearing immunoglobulins with the highest affinity for antigen receive positive selection signals from T helper cells that promotes their rapid proliferation. Here we show that the RNA binding protein PTBP1 is necessary for the progression of GC B cells through late S-phase of the cell cycle and for affinity maturation. PTBP1 is required for the expression of the c-MYC-dependent gene programme induced in GC B cells receiving T cell help and directly regulates the alternative splicing of transcripts increased during positive selection to promote anabolic metabolism and cell proliferation.
2017-12-06 | GSE100969 | GEO
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.
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