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TGF-β-induced MIR99AHG synergizes with PTBP1 to trigger an alternative splicing switch of SMARCA1 that promotes invadopodia formation for metastasis in colorectal cancer

ABSTRACT: TGF-β-induced MIR99AHG synergizes with PTBP1 to trigger an alternative splicing switch of SMARCA1 that promotes invadopodia formation for metastasis in colorectal cancer

PROVIDER: PRJNA1003889 | ENA |

REPOSITORIES: ENA

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TGF-β-induced MIR99AHG synergizes with PTBP1 to trigger an alternative splicing switch of SMARCA1 that promotes invadopodia formation for metastasis in colorectal cancer

Project description:Alternative splicing (AS) of pre-mRNAs is an essential process that regulates gene expression and functional diversity, yet the underlying regulatory mechanisms that control this process during cancer metastasis are not clear. Here, we uncovered that a long non-coding RNA (lncRNA), MIR99AHG, mediates regulation of AS to alter chromatin remodeler function and promote invadopodia formation in colorectal cancer (CRC). We found that MIR99AHG is highly expressed in metastatic CRC cells and patient tissue samples. In vitro and in vivo assays showed that MIR99AHG potently drove CRC cell motility, invasion, and metastasis. MIR99AHG bound to and stabilized the RNA splicing factor PTBP1, which cooperatively increased cassette exon inclusion of the chromatin remodeling gene SMARCA1. Mechanistically, MIR99AHG acted as an address label for PTBP1 to fine-tune its binding pattern on SMARCA1 pre-mRNA, thereby controlling the skipping-to-inclusion splicing switch of SMARCA1 and favouring the production of a long isoform (SMARCA1-L). Canonical SMARCA1 was found to suppress cell migration and invasiveness by inhibiting invadopodia formation, but SMARCA1-L was functionally inert. Clinical data revealed that MIR99AHG was positively correlated with PTBP1 and SMARCA1-L in human CRC specimens and predicted patient outcome. Furthermore, we showed that the crosstalk with cancer-associated fibroblasts triggers TGF-β/SMAD signalling in CRC cells and activates MIR99AHG expression. Our findings establish a novel mechanism for a lncRNA that interacts with PTBP1 to regulate AS process, providing a potential therapeutic target and predictive biomarker of CRC.

2025-08-08 | GSE240485 | GEO

iiCLIP protocol benchmarking with PTBP1

Project description:We describe an improved individual nucleotide resolution CLIP protocol (iiCLIP), which can be completed within 4 days from UV crosslinking to libraries for sequencing. For benchmarking, we directly compared PTBP1 iiCLIP libraries with the iCLIP2 protocol produced under standardised conditions with 1 million HEK293 cells, and with public eCLIP and iCLIP PTBP1 data. There are 3 PTBP1 iiCLIP libraries, 1 input iiCLIP library and 1 PTBP1 iCLIP2 library produced in this study.

2022-08-01 | E-MTAB-10881 | biostudies-arrayexpress

Proteome changes in PTBP1 deficient hematopoietic cells

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

PTBP1 - Modified iCLIP

Project description:PTBP1 - Modified iCLIP

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Regulation of co-transcriptional splicing by RNA-binding protein PTBP1

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

GNPS Phoenicin switch: Penicillium atrosanguineum on various growth media

Project description:Part of the publication: Phoenicin Switch: Discovering the trigger for radical phoenicin production in multiple wild type Penicillium species.

2022-04-25 | MSV000089306 | GNPS

Transcriptomic analysis of senescent cells upon PTBP1 knockdown.

Project description:IMR90 ER:RAS cells were stably transduced with either an empty vector or 2 deconvoluted shRNAs targeting PTBP1. Following selection with puromycin, the cells were treated with 4OHT to induce senescence. 6 days later the cells were collected for total mRNA analysis. PTBP1 is a regulator of alternative splicing. Our previous experiments had shown that PTBP1 depletion inhibits the expression of pro-inflammatory genes without affecting other senescence-associated phenotypes. By performing RNA-seq we confirmed those observations at a global level and analysed how PTBP1 knockdown alters alternative splicing as a potential mechanism of action.

2018-06-25 | GSE101750 | GEO

GNPS Phoenicin switch: Penicillium atrosanguineum on various growth media dataset 2

Project description:Part of publication: Phoenicin Switch: Discovering the trigger for radical phoenicin production in multiple wild type Penicillium species.

2022-04-25 | MSV000089310 | GNPS

Effect of degradation of IGFRIL/PTBP1 in HepG2 cells

Project description:To investigate the effect of IGFRIL/PTBP1 in HCC, we established HepG2 cell lines in which IGFRIL/PTBP1 mRNA has been degraded using siRNA.

2023-05-13 | GSE232354 | GEO

Detection of transcriptome changes caused by knockdown of Ptbp1 in U251 GBM cells

Project description:We demonstrated that knocking down Ptbp1 can reprogram GBM cells into neuron-like cells. In order to further explore the mechanism of Ptbp1 causing this phenomenon, we performed mRNA sequencing on U251 cells infected with sh-Luci-3d, sh-Ptbp1-3d and sh-Ptbp1-7d.

2022-06-01 | GSE189816 | GEO

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