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The Splicing Factor PTBP1 Interacts with RUNX1 and is Required for Leukemia Cell Survival [CUT&Tag]

ABSTRACT: Runt-related Transcription Factor 1 (RUNX1) is essential for definitive hematopoiesis and is among the most frequently mutated genes in leukemia. Previous work from our lab demonstrated that Histone Deacetylase 1 (HDAC1), a known RUNX1 partner, is unexpectedly required for active transcription suggesting a non-histone role for HDAC1 regulating components of the RUNX1 complex. Here, we use proteomics, genomics, and long-read transcriptomics to identify novel RUNX1 interacting partners and decipher their role in gene regulation and RNA splicing in leukemia cells. We demonstrate that Polypyrimidine Tract Binding Protein 1 (PTBP1) interacts with RUNX1 in an HDAC1-dependent manner. Chromatin profiling revealed extensive genome-wide overlap in sites occupied by RUNX1 and PTBP1, with significant enrichment at promoters of actively transcribed genes. Loss of PTBP1 in AML cells led to widespread alterations in RNA splicing and decreased expression of genes whose promoters are bound by both factors, including metabolic genes. In agreement with these findings, we found that loss of PTBP1 reduced glycolysis and glucose uptake and ultimately caused cell death. Based on our data, we propose that the interaction between RUNX1 and PTBP1 facilitates expression of metabolic proteins essential for leukemia cell growth and survival.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308248 | GEO | 2025/11/11

REPOSITORIES: GEO

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The Splicing Factor PTBP1 Interacts with RUNX1 and is Required for Leukemia Cell Survival [Long Read]

Project description:Runt-related Transcription Factor 1 (RUNX1) is essential for definitive hematopoiesis and is among the most frequently mutated genes in leukemia. Previous work from our lab demonstrated that Histone Deacetylase 1 (HDAC1), a known RUNX1 partner, is unexpectedly required for active transcription suggesting a non-histone role for HDAC1 regulating components of the RUNX1 complex. Here, we use proteomics, genomics, and long-read transcriptomics to identify novel RUNX1 interacting partners and decipher their role in gene regulation and RNA splicing in leukemia cells. We demonstrate that Polypyrimidine Tract Binding Protein 1 (PTBP1) interacts with RUNX1 in an HDAC1-dependent manner. Chromatin profiling revealed extensive genome-wide overlap in sites occupied by RUNX1 and PTBP1, with significant enrichment at promoters of actively transcribed genes. Loss of PTBP1 in AML cells led to widespread alterations in RNA splicing and decreased expression of genes whose promoters are bound by both factors, including metabolic genes. In agreement with these findings, we found that loss of PTBP1 reduced glycolysis and glucose uptake and ultimately caused cell death. Based on our data, we propose that the interaction between RUNX1 and PTBP1 facilitates expression of metabolic proteins essential for leukemia cell growth and survival.

2025-11-11 | GSE308249 | GEO

Enhancer recruitment of transcription repressors RUNX1 and TLE3 by mis-expressed FOXC1 blocks differentiation in acute myeloid leukemia

Project description:Despite absent expression in normal hematopoiesis, the Forkhead factor FOXC1, a critical mesenchymal differentiation regulator, is highly expressed in ~30% of HOXAhigh AML to confer blocked monocyte/macrophage differentiation. Through integrated proteomics and bioinformatics, we discovered that FOXC1 and RUNX1 interact through Forkhead and Runt domains respectively and cooccupy primed and active enhancers distributed close to differentiation genes. FOXC1 stabilises association of RUNX1, HDAC1 and Groucho repressor TLE3 to limit enhancer activity: FOXC1 knockdown induced loss of repressor proteins, gain of CEBPA binding, enhancer acetylation and upregulation of nearby genes, including KLF2. Furthermore, it triggered genome-wide redistribution of RUNX1, TLE3 and HDAC1 from enhancers to promoters leading to repression of self-renewal genes including MYC and MYB. Our studies highlight RUNX1 and CEBPA transcription factor swapping as a feature of leukemia cell differentiation, and reveal that FOXC1 prevents this by stabilising enhancer binding of a RUNX1/HDAC1/TLE3 transcription repressor complex, to oncogenic effect.

2021-08-08 | PXD027740 | Pride

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

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

Splicing factor PTBP1 promotes hepatocarcinogenesis via oncogenic splice-switching of MAPT

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

PTBP1 promotes hematopoietic stem cell maintenance and red blood cell development by ensuring sufficient availability of ribosomal constituents

Project description:Ribosomopathies constitute a range of disorders 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 decreases 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.

2022-05-05 | GSE165682 | GEO

PTBP1 Regulates DNMT3B Alternative Splicing by Interacting with RALY to Enhance the Radioresistance of Prostate Cancer

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

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

PTBP1 controls intestinal epithelial regeneration through post-transcriptional regulation of gene expression

Project description:The intestinal epithelial regeneration is driven by intestinal stem cells under homeostatic conditions. Differentiated intestinal epithelial cells, such as Paneth cells, are capable of acquiring multipotency and contributing to regeneration upon loss of intestinal stem cells. Paneth cells also support intestinal stem cell survival and regeneration. We report here that depletion of an RNA-binding protein named polypyrimidine tract binding protein 1 (PTBP1) in mouse intestinal epithelial cells causes intestinal stem cell death and epithelial regeneration failure. Mechanistically, we show that PTBP1 inhibits neuronal-like splicing programs in intestinal crypt cells, which is critical for maintaining intestinal stem cell stemness. This function is achieved at least in part through promoting the non-productive splicing of its paralog PTBP2. Moreover, PTBP1 inhibits the expression of an AKT inhibitor PHLDA3 in Paneth cells and permits AKT activation, which presumably maintains Paneth cell plasticity and function in supporting intestinal stem cell niche. We show that PTBP1 directly binds to a CU-rich region in the 3’ UTR of Phlda3, which we demonstrate to be critical for downregulating the mRNA and protein levels of Phlda3. Our results thus reveal the multifaceted in vivo regulation of intestinal epithelial regeneration by PTBP1 at the post-transcriptional level.

2023-01-18 | GSE185499 | GEO

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

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