Targeting RBPMS selectively eliminates leukemia initiating cells via the USP1/m6A/FOXO1 axis
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ABSTRACT:
PROVIDER: PRJNA962062 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24310674_1.fastq.gz | Fastqsanger.gz | |||
| SRR24310674_2.fastq.gz | Fastqsanger.gz | |||
| SRR24310675_1.fastq.gz | Fastqsanger.gz | |||
| SRR24310675_2.fastq.gz | Fastqsanger.gz | |||
| SRR24310676_1.fastq.gz | Fastqsanger.gz |
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Project description:Acute myeloid leukemia (AML) is a malignant tumor with high recurrence rate and poor prognosis. RNA-binding proteins (RBPs) are essential modulators of transcription and translation played critical roles and frequently dysregulated in AML. Here we show that RBPMS (RNA binding protein with multiple splicing) which is highly expressed in AML and associated with poor prognosis of AML, plays critical roles in leukemogenesis. Our study shows that inhibition of RBPMS abrogates self-renewal of leukemia initiating cells (LICs) and AML development but has little effect on normal hematopoiesis. Mechanistically, RBPMS maintains the stability of the m6A reader IGF2BP3 by USP1-mediated deubiquitination, which promotes the translation of the FOXO1 mRNA in an m6A-dependent manner. Moreover, RBPMS contributes to the progression of leukemia by promoting FOXO1/ENO2/ALDOC regulated glycolysis. Overexpression of FOXO1 has been shown to rescue RBPMS inhibition-induced phenotypes in both leukemia cells and mouse models. We have also designed a specific inhibitor of RBPMS that has therapeutic effects in the AML patient derived xenograft model (PDX) model. We, therefore, we highlight RBPMS as a promising drug target for AML therapy.
2023-10-04 | GSE230646 | GEO
Project description:CRISPR Cas9-based functional genomics screening is a powerful approach for identifying and characterizing novel oncology drug targets. Here, we elucidate the synthetic lethal mechanism of deubiquitinating enzyme USP1 in cancers with underlying DNA damage vulnerabilities, specifically BRCA1/2 mutant tumors and a subset of BRCA1/2 wild-type (WT) tumors. In sensitive cells, pharmacological inhibition of USP1 leads to decreased DNA synthesis concomitant with the induction of S-phase-specific DNA damage. Genome-wide CRISPR-Cas9 screens identified RAD18 and UBE2K, which promote PCNA mono- and polyubiquitination respectively, as downstream mediators of USP1 dependency. The accumulation of mono- and polyubiquitinated PCNA following USP1 inhibition was associated with a reduction in total PCNA protein levels. Ectopic expression of WT and ubiquitin-dead K164R PCNA reversed USP1 inhibitor sensitivity. Our results demonstrate, for the first time, that USP1 dependency hinges on the aberrant processing of mono- and polyubiquitinated PCNA. Moreover, this mechanism of USP1 dependency extends beyond BRCA1/2 mutant tumors to a novel subset of BRCA1/2 WT cancer enriched in ovarian and lung lineages. We further show PARP and USP1 inhibition are strongly synergistic in BRCA1/2 mutant cell lines and xenograft models. We postulate USP1 dependency unveils a previously uncharacterized vulnerability linked to post-translational modifications of PCNA. Taken together, USP1 inhibition may represent a unique therapeutic strategy for BRCA1/2 mutant tumors and a subset of BRCA1/2 WT tumors.
2022-09-27 | GSE214121 | GEO
Project description:Background: Modulation of mRNA splicing acts as an important layer of gene regulation, in addition to transcriptional regulation and epigenetic modifications. RNA binding proteins (RBPs) play essential roles in mediating RNA splicing and are key regulators of heart development and function. Our previous studies demonstrated that RBPMS (RNA-binding protein with multiple splicing) regulates cardiac development through modulating mRNA splicing during embryogenesis. Here we explored the postnatal function of RBPMS in the heart. Methods: We ablated Rbpms in the heart by generating a cardiac-specific knockout mouse line (Myh6-Cre, Rbpmsfl/fl), and evaluated its cardiac functions by histology, echocardiography, and gene expression. Paired-end RNA sequencing and RT-PCR were performed to identify and validate splicing targets of RBPMS in adult mouse hearts. Proximity-dependent Biotin Identification (BioID) assay and mass spectrometry analysis were performed to identify RBPMS binding partners. We also measured contractility and calcium fluxes in isolated mouse cardiomyocytes, and contractile forces of cardiac papillary muscle. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) were also used as a model to explore the influence of RBPMS on contractility of human cardiomyocytes. Results: he absence of Rbpms in the heart led to dilated cardiomyopathy (DCM) and heart failure, causing early death in mice. Mice with cardiac-specific knockout of Rbpms showed myocardium noncompaction with reduced cardiomyocyte number at the neonatal stage and developed DCM with pervasive myocardial fibrosis in adulthood. We found that RBPMS mediates a largely distinct RNA splicing profile in adult mouse hearts compared to neonatal hearts, indicating a stage-specific modulation of alternative RNA splicing by RBPMS. In adult hearts, RBPMS mainly influenced alternative splicing of genes associated with sarcomere structures and cardiomyocyte contraction, such as Ttn, Pdlim5 and Nexn, to generate new protein isoforms. In neonatal hearts, RBPMS influenced the splicing of cytoskeletal genes. RBMPS was associated with spliceosome factors and other RNA binding proteins that play important roles in the heart, such as RBM20 and GATA4. Importantly, we found that the absence of Rbpms caused severe cardiomyocyte contractile defects and reduced calcium sensitivity in both mouse and hiPSC-CMs. Our results demonstrated that Rbpms is crucial for postnatal cardiac function and cardiomyocyte contractility by regulating RNA alternative splicing. Conclusions: Loss of Rbpms in the heart causes reduced cardiomyocyte number and impaired cardiomyocyte contraction, leading to DCM and heart failure.
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Project description:Investigation of RBPMS role in post-transcriptional control of mRNAs in rat PAC1 pulmonary artery smooth muscle cells (SMCs). PolyA mRNA-Seq was carried out after RBPMS knockdown in differentiated PAC1 cells and after inducible RBPMS-A overexpression in dedifferentiated (proliferative) PAC1 cells.
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Project description:To explore the function of deubiquitinase USP1 in breast cancer cells, we performed RNA sequencing to analyze the expression pattern changes by knockdown of USP1 in MCF7 cells.
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Project description:To investigate the function of USP1 in the HCC.
2022-11-23 | GSE218366 | GEO
Project description:Gastric cancer is one of the leading causes of cancer-related deaths, and through in vivo and in vitro genetic screens, we identified USP1 as an important factor in promoting tumor progression. Here, we analyzed the transcriptome of sh-USP after knockdown with the aim of identifying downstream effectors of USP1
2024-12-01 | GSE282776 | GEO
Project description:Differentiated Vascular Smooth Muscle Cells (VSMCs) express a unique network of splice isoforms (smooth muscle specific alternative splicing - SM-AS) in functionally critical genes including those comprising the contractile machinery. We previously described RNA Binding Protein Multiple Splicing (RBPMS) as a potent driver of contractile, aortic tissue like SM-AS in VSMCs using rodent models. What is unknown is how RBPMS affects VSMC phenotype and behaviour. Here, we use human embryonic stem cell-derived VSMCs (hES-VSMCs) to dissect the role of RBPMS in SM-AS in human cells and determine the impact on VSMC phenotypic properties. hES-VSMCs are inherently immature and display only partially differentiated SM-AS patterns while RBPMS levels are undetectable endogenously. Hence, we used an over-expression system and found that RBPMS induces SM-AS patterns in hES-VSMCs akin to the contractile tissue VSMC splicing patterns in multiple events. We present in silico and experimental findings that support RBPMS’ splicing activity as mediated through direct binding and via functional cooperativity with splicing factor RBFOX2 on a significant subset of targets. Finally, we demonstrate that RBPMS can alter the motility and the proliferative properties of hES-VSMCs to mimic a more differentiated state. Overall, this study emphasizes a critical splicing regulatory role for RBPMS in human VSMCs and provides evidence of phenotypic modulation by RBPMS.
2024-12-19 | GSE242826 | GEO
Project description:Ewing sarcoma (EWS) is a malignant pediatric bone cancer. Most Ewing sarcomas are driven by EWS-FLI1 oncogenic transcription factor that plays roles in transcriptional regulation, DNA damage response, cell cycle checkpoint control, and alternative splicing. USP1, a deubiquitylase which regulates DNA damage and replication stress responses, is overexpressed at both the mRNA and protein levels in EWS cell lines compared to human mesenchymal stem cells, the EWS cell of origin. The functional significance of high USP1 expression in Ewing sarcoma is not known. Here, we identify USP1 as a transcriptional target of EWS-FLI1 and a key regulator of EWS cell survival. We show that EWS-FLI1 knockdown decreases USP1 mRNA and protein levels. ChIP and ChIP-seq analyses show EWS-FLI1 occupancy on the USP1 promoter. Importantly, USP1 knockdown or inhibition arrests EWS cell growth and induces cell death by apoptosis. We observe destabilization of Survivin (also known as BIRC5 or IAP4) and activation of caspases-3 and -7 following USP1 knockdown or inhibition in the absence of external DNA damage stimuli. Notably, EWS cells display hypersensitivity to combinatorial treatment of doxorubicin or etoposide, EWS standard of care drugs, and USP1 inhibitor compared to single agents alone. Together, our study demonstrates that USP1 is regulated by EWS-FLI1, the USP1-Survivin axis promotes EWS cell survival, and USP1 inhibition sensitizes EWS cells to standard of care chemotherapy.
2024-01-26 | PXD041033 | Pride
Project description:Retinal ganglion cells (RGCs) are the sole output neurons conveying visual stimuli from the retina to the brain and the dysfunction or loss of RGCs is the primary determinant of visual loss in traumatic and degenerative ocular conditions. Currently, there is a lack of RGC-specific Cre mouse lines that serve as invaluable tools for manipulating genes in RGCs and studying the genetic basis of RGC diseases. The RNA-binding protein with multiple splicing (RBPMS) is identified as the specific marker of all RGCs. Here, we report the generation and characterization of a knock-in mouse line in which a P2A-CreERT2 coding sequence is fused in-frame to the C-terminus of endogenous RBPMS, allowing the co-expression of RBPMS and CreERT2. The inducible Rbpms-CreERT2 mice exhibited a high recombination efficiency in activating the expression of tdTomato reporter gene in nearly all adult RGCs as well as in differentiated RGCs starting at E13.5. Additionally, heterozygous Rbpms-CreERT2 knock-in mice showed no detectable defect in the retinal structure, visual function and transcriptome. Altogether, our results demonstrated that the Rbpms-CreERT2/+ knock-in mouse can serve as a powerful and highly desired genetic tool for lineage tracing, genetic manipulation, retinal physiology study and ocular disease modeling in RGCs.
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