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Splice Factor Polypyrimidine tract-binding protein 1 (Ptbp1) Primes Endothelial Inflammation in Atherogenic Disturbed Flow Conditions [CRISPR]

ABSTRACT: Analysis of effects of Ptbp1 deletion on RNA splicing and expression in aortic endothelial cells

ORGANISM(S): Mus musculus

PROVIDER: GSE206850 | GEO | 2022/06/27

REPOSITORIES: GEO

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Splice Factor Polypyrimidine tract-binding protein 1 (Ptbp1) Primes Endothelial Inflammation in Atherogenic Disturbed Flow Conditions [Ptbp1]

Project description:Analysis of effects of Ptbp1 deletion on RNA splicing and expression in aortic endothelial cells

2022-06-27 | GSE206849 | GEO

Splice factor polypyrimidine tract-binding protein 1 (Ptbp1) primes endothelial inflammation in atherogenic disturbed flow conditions.

Project description:NF-κB-mediated endothelial activation drives leukocyte recruitment and atherosclerosis, in part through adhesion molecules Icam1 and Vcam1. The endothelium is primed for cytokine activation of NF-κB by exposure to low and disturbed blood flow (LDF)but the molecular underpinnings are not fully understood. In an experimental in vivo model of LDF, platelets were required for the increased expression of several RNA-binding splice factors, including polypyrimidine tract binding protein (Ptbp1). This was coordinated with changes in RNA splicing in the NF-κB pathway in primed cells, leading us to examine splice factors as mediators of priming. Using Icam1 and Vcam1 induction by tumor necrosis factor (TNF)-α stimulation as a readout, we performed a CRISPR Cas9 knockout screen and identified a requirement for Ptbp1 in priming. Deletion of Ptbp1 had no effect on cell growth or response to apoptotic stimuli, but reversed LDF splicing patterns and inhibited NF-κB nuclear translocation and transcriptional activation of downstream targets, including Icam1 and Vcam1. In human coronary arteries, elevated PTBP1 correlates with expression of TNF pathway genes and plaque. In vivo, endothelial-specific deletion of Ptbp1 reduced Icam1 expression and myeloid cell infiltration at regions of LDF in atherosclerotic mice, limiting atherosclerosis. This may be mediated, in part, by allowing inclusion of a conserved alternative exon in Ripk1 leading to a reduction in Ripk1 protein. Our data show that Ptbp1, which is induced in a subset of the endothelium by platelet recruitment at regions of LDF, is required for priming of the endothelium for subsequent NF-κB activation, myeloid cell recruitment and atherosclerosis.

| S-EPMC9335344 | biostudies-literature

Splice Factor Polypyrimidine tract-binding protein 1 (Ptbp1) Primes Endothelial Inflammation in Atherogenic Disturbed Flow Conditions

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-06-27 | GSE206851 | GEO

Splice Factor Polypyrimidine tract-binding protein 1 (Ptbp1) Primes Endothelial Inflammation in Atherogenic Disturbed Flow Conditions [Ptbp1]

Project description:Splice Factor Polypyrimidine tract-binding protein 1 (Ptbp1) Primes Endothelial Inflammation in Atherogenic Disturbed Flow Conditions [Ptbp1]

| PRJNA852427 | ENA

Splice Factor Polypyrimidine tract-binding protein 1 (Ptbp1) Primes Endothelial Inflammation in Atherogenic Disturbed Flow Conditions

Project description:Splice Factor Polypyrimidine tract-binding protein 1 (Ptbp1) Primes Endothelial Inflammation in Atherogenic Disturbed Flow Conditions

| PRJNA852424 | ENA

Splice Factor Polypyrimidine tract-binding protein 1 (Ptbp1) Primes Endothelial Inflammation in Atherogenic Disturbed Flow Conditions [CRISPR]

Project description:Splice Factor Polypyrimidine tract-binding protein 1 (Ptbp1) Primes Endothelial Inflammation in Atherogenic Disturbed Flow Conditions [CRISPR]

| PRJNA852426 | ENA

Polypyrimidine Tract Binding Proteins PTBP1 and PTBP2 Interact with Distinct Proteins Under Splicing Conditions

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

Polypyrimidine tract binding proteins are essential for B cell development

Project description:During B cell development, recombination of immunoglobulin loci is tightly coordinated with the cell cycle to avoid unwanted rearrangements of other genomic locations. Several factors have been identified that suppress proliferation in late-pre-B cells to allow light chain recombination. By comparison, our knowledge of factors limiting proliferation during heavy chain recombination at the pro-B cell stage is very limited. Here we identify an essential role for the RNA-binding protein Polypyrimidine Tract Binding Protein 1 (PTBP1) in B cell development. Absence of PTBP1 and the paralog PTBP2 results in a complete block in development at the pro-B cell stage. PTBP1 promotes the fidelity of the transcriptome in pro-B cells. In particular, PTBP1 controls a cell cycle mRNA regulon, suppresses entry into S-phase and promotes progression into mitosis. Our results highlight the importance of S-phase entry suppression and post-transcriptional gene expression control by PTBP1 in pro-B cells for proper B cell development.

2020-02-21 | GSE136882 | GEO

Polypyrimidine Tract Binding Protein 1 regulates the activation of mouse CD8 T cells

Project description:We show that the RNA-binding protein Polypyrimidine Tract Binding Protein 1 (PTBP1) is dispensable for the development of naïve mouse CD8 T cells, but is necessary for the optimal expansion and production of effector molecules by antigen-specific CD8 T cells in vivo. PTBP1 has an essential role in regulating the early events following activation of the naïve CD8 T cell leading to IL-2 and TNF production. It is also required to protect activated CD8 T cells from apoptosis. PTBP1 controls alternative splicing of over 400 genes in naïve CD8 T cells in addition to regulating the abundance of ~200 mRNAs. PTBP1 is required for the nuclear accumulation of c-Fos, NFATc2 and NFATc3, but not NFATc1. This selective effect on NFAT proteins correlates with PTBP1-promoted expression of the shorter Ab1 isoform and exon 13 skipped Ab2 isoform of the catalytic A-sububit of calcineurin phosphatse. These findings reveal a crucial role for PTBP1 in regulating CD8 T cell activation.

2021-12-09 | GSE190512 | GEO

Post-Translational Modifications in Polypyrimidine Tract Binding Proteins PTBP1 and PTBP2.

Project description:RNA binding proteins play an important role in regulating alternative pre-mRNA splicing and in turn cellular gene expression. Many of these RNA binding proteins occur as gene families with members sharing a high degree of primary structure identity and domain organization yet have tissue-specific expression patterns and regulate different sets of target exons. How highly similar members in a gene family can exert different splicing outcomes is not well understood. We conducted mass spectrometry analysis of post-translational phosphorylation and acetylation modifications for two paralogs of the polypyrimidine tract binding protein family, PTBP1 and PTBP2, to discover modifications that occur in splicing reaction mixtures and to identify discrete modifications that may direct their different splicing activities. We find that PTBP1 and PTBP2 have many distinct phosphate modifications located in the unstructured N-terminal, linker 1, and linker 2 regions. We find that the two proteins have many overlapping acetate modifications in the RNA recognition motifs (RRMs) with a few distinct sites in PTBP1 RRM2 and RRM3. Our data also reveal that lysine residues in the nuclear localization sequence of PTBP2 are acetylated. Collectively, our results highlight important differences in post-translational modifications between the paralogs and suggest a role for them in the differential splicing activity of PTBP1 and PTBP2.

| S-EPMC6211845 | biostudies-literature

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