PRMT1-Mdm4-p53 pathway controls epicardial invasion and cell fate transition
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA503912 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8162740.fastq.gz | Fastqsanger.gz | |||
| SRR8162750.fastq.gz | Fastqsanger.gz | |||
| SRR8162741.fastq.gz | Fastqsanger.gz | |||
| SRR8162751.fastq.gz | Fastqsanger.gz | |||
| SRR8162742.fastq.gz | Fastqsanger.gz |
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Project description:Epicardial cells are progenitors giving rise to the majority of cardiac fibroblasts, coronary smooth muscle cells, and pericytes during cardiac development, and critically modulating heart morphogenesis and coronary development. An integral phase of epicardial cell fate transition is epithelial-to-mesenchymal transition (EMT), which confers motility and facilitates cell fate transition. We identify a pathway involving protein arginine methyltransferase 1 (PRMT1) and its downstream p53 signaling that drives epicardial EMT and invasion. We show that PRMT1 determines the half-life of p53 through regulating alternative splicing of Mdm4, which is a key controller of p53 degradation. Loss of PRMT1 promotes the expression of Mdm4 short form, which inhibits p53 degradation. Accumulation of p53 subsequently enhances Slug degradation and blocks epicardial EMT. We further demonstrated that the PRMT1-Mdm4-p53 pathway drives epicardial cell fate transition into cardiac fibroblasts, coronary smooth muscle cells and pericytes in vivo, and modulates ventricular morphogenesis and coronary vessel formation. Together, our results establish critical functions of the PRMT1-Mdm4-p53 pathway in epicardial EMT, invasion and cell fate transition.
2020-08-18 | GSE122200 | GEO
Project description:To study the role of PRMT1 in epicardial fate decision during development using Single cell RNA-seq analysis
2020-08-18 | GSE144271 | GEO
Project description:Epicardial cells are cardiac progenitors that give rise to the majority of cardiac fibroblasts, coronary smooth muscle cells, and pericytes during development. An integral phase of epicardial fate transition is epithelial-to-mesenchymal transition (EMT) that confers motility. We uncover an essential role for the protein arginine methyltransferase 1 (PRMT1) in epicardial invasion and differentiation. Using scRNA-seq, we show that epicardial-specific deletion of Prmt1 reduced matrix and ribosomal gene expression in epicardial-derived cell lineages. PRMT1 regulates splicing of Mdm4, which is a key controller of p53 stability. Loss of PRMT1 leads to accumulation of p53 that enhances Slug degradation and blocks EMT. During heart development, the PRMT1-p53 pathway is required for epicardial invasion and formation of epicardial-derived lineages: cardiac fibroblasts, coronary smooth muscle cells, and pericytes. Consequently, this pathway modulates ventricular morphogenesis and coronary vessel formation. Altogether, our study reveals molecular mechanisms involving the PRMT1-p53 pathway and establish its roles in heart development.
| S-EPMC7425665 | biostudies-literature
Project description:We report 6 unrelated individuals with variable BMF phenotypes and hypocellular MDS. The median age at presentation was 10 years (4 weeks - 53 years). Unbiased genomic analysis revealed germline heterozygous variants in MDM4, including 4 null (frameshift, nonsense, and splice-site resulting in premature truncation confirmed by RNA sequencing) and 2 missense variants. Mechanistically, MDM4 mutations lead to loss-of-function with enhanced p53 activation. We used CRISPR/Cas9 to delete MDM4 in healthy donor hematopoietic stem and progenitor cells (HSPCs). The resulting MDM4-haploinsufficient HSPCs exhibited increased p53 activity, impaired colony-forming capacity, and reduced engraftment potential in immunodeficient mice. Complementation studies revealed the functional necessity of both p53-binding and RING-finger domains in MDM4-mediated hematopoietic regulation. To study variant effect in a genetic background free of potential confounders, we introduced patient-specific MDM4 variants into induced pluripotent stem cells (iPSCs). MDM4-mutant iPSCs yielded significantly reduced erythroid and myeloid cell populations and exhibited increased p53 activity, as evidenced by elevated p21 expression, confirming the role of MDM4 in regulating hematopoiesis through p53 modulation. Transcriptome analysis of iPSC-derived hematopoietic cells revealed upregulation of p53 pathway. Importantly, one patient acquired TP53 mutations, suggesting clonal rescue in the context of MDM4 deficiency. Our findings establish MDM4 deficiency as a new “TP53-opathy” BMF syndrome with variable hematopoietic manifestations. This study also highlights the critical role of the MDM4-p53 axis in maintaining hematopoietic homeostasis.
2025-10-16 | GSE279650 | GEO
Project description:Ubiquitination plays an important role in proliferating and invasive characteristic of glioblastoma (GBM), similar to many other cancers. Tripartite motif 25 (TRIM25) is a member of the TRIM family of proteins, which are involved in tumorigenesis through substrate ubiquitination. Here, we found TRIM25 is upregulated in GBM and promotes glioblastoma cell growth and invasion, both in vitro and in vivo. Subsequently, we screened a panel of proteins that interact with TRIM25; mass spectrometry and co-immunoprecipitation showed that NONO was a potential substrate of TRIM25. TRIM25 knockdown reduced the K63-linked ubiquitination of NONO, which suppressed the splicing function of NONO. The dysfunctional NONO further leads to the retention of the second intron in the pre-mRNA of PRMT1 and inhibit the activation of the PRMT1/c-MYC pathway. In summary, we demonstrated that TRIM25 promotes glioblastoma cell growth and invasion by regulating the PRMT1/c-MYC pathway through mediation of the splicing factor NONO. Efforts to target the E3 ligase activity of TRIM25 or the complex interactions between TRIM25 and NONO may be useful in the treatment of GBM.
2023-07-11 | GSE236661 | GEO
Project description:The interplay between multiple transcription factors precisely regulates eukaryotic transcription. Here, we report that the protein methyltransferases, MLL2 and PRMT1, interact directly and act collectively to regulate gene expression. PRMT1 binds to the N-terminal region of MLL2, considered an intrinsically disordered region, and methylates multiple arginine residues within its RGG/RG motifs. Notably, overexpression of PRMT1 decreased poly-ubiquitylation of MLL2, whereas mutations on methylation sites in MLL2 increased MLL2 poly-ubiquitylation, suggesting that PRMT1-mediated methylation stabilizes MLL2. MLL2 and PRMT1 cooperatively stimulated the expression of a chromosomal reporter gene in a PRMT1-mediated, MLL2-methylation–dependent manner. RNA-seq analysis found that MLL2 and PRMT1 jointly regulate the expression of genes involved in cell membrane and extracellular matrix functions, and depletion of either resulted in impaired cell migration and invasion. Our study provides evidence that PRMT1-mediated MLL2 methylation regulates MLL2 protein stability and the expression of their target genes.
2024-10-21 | GSE274754 | GEO
Project description:PRMT1 is thought to be responsible for the majority of PRMT activity in Toxoplasma gondii, but its exact function is unknown. We generated T. gondii mutants lacking PRMT1 (∆prmt1) by deletion of the PRMT1 gene. ∆prmt1 parasites exhibit morphological defects during cell division and grow slowly, and this phenotype reverses in the complemented strain ∆prmt::PRMT1mRFP. PRMT1 localizes primarily in the cytoplasm with enrichment at the centrosome, and the strain lacking PRMT1 is unable to segregate progeny accurately. Unlike wild-type and complemented parasites, ∆prmt1 parasites have abnormal daughter buds, perturbed centrosome stoichiometry, and loss of synchronous replication. Whole genome expression profiling demonstrated differences in expression of cell cycle regulated genes in ∆prmt1 relative to the complemented ∆prmt1::PRMT1mRFP and parental wild-type strains, but these changes did not correlate with a specific block in cell cycle. Although PRMT1’s primary biological function was previously proposed to be methylation of histones, our genetic studies suggest that the most critical function of PRMT1 is within the centrosome as a regulator of daughter cell counting to assure the proper replication of the parasite. RNA samples were isolated in triplicates from RH-hxgprt parent strain (W), PRMT1 knockout (K) strain and PRMT1 knockout strain complemented with RFP-tagged PRMT1 protein (C). Parasites were grown for 32h at 37C. Samples were hybridized to the Toxoplasma gondii Affymetrix microarray (ToxoGeneChip: http://ancillary.toxodb.org/docs/Array-Tutorial.html). Hybridization data was preprocessed with Robust Multi-array Average (RMA) and normalized using per chip and per gene median polishing and analyzed using the software package GeneSpring GX (Agilent Technologies).
2015-09-18 | E-GEOD-73177 | biostudies-arrayexpress
Project description:Defects in the splicing machinery have been implicated in various diseases, including cancer. We identified a general reduction in the expression spliceosome components and splicing regulators in human cell lines undergoing replicative, stress-induced and telomere uncapping-induced senescence. Supporting the notion that defective splicing contributes to senescence, we showed that the splicing inhibitors herboxidiene and pladienolide B induce senescence both in normal and cancer cell lines. Furthermore, the individual depletion of several spliceosome components also promoted senescence. We noted an alternative splicing shift in MDM4, from the full-length MDM4-FL variant to MDM4-S during replicative and stress-induced senescence. This shift was replicated by splicing inhibition and the depletion of individual spliceosome components. Importantly, decreasing the level of MDM4-FL promoted senescence, while cell survival was improved both by reducing the level of MDM4-FL and by overexpressing MDM4-S. Overall, our work establishes that defects in the splicing machinery alter the alternative splicing of MDM4 to promote senescence.
2024-10-11 | GSE245356 | GEO
Project description:The epicardium is the mesothelial lining of the heart which acts as a source of progenitor cells during heart development, giving rise to an invasive population of mesenchymal cells which differentiate into cardiac fibroblasts, mural cells, and other cell types essential for heart structure and function. Previously, we showed that epicardial-specific deletion of the gene encoding SRY-box transcription factor 9 (SOX9) impairs epicardial-derived cell invasion and reduces their contribution to the atrioventricular valve mesenchyme. In this study, we use single-cell RNA-sequencing to investigate broader roles of Sox9 in the epicardium as it relates to epicardial invasion, differentiation, and vascular development. We identified transcriptional changes indicative of decreased epicardial-to-mesenchymal transformation consistent with histological observations. Sox9-deficient epicardial cells exhibited elevated expression of vascular smooth muscle cell genes, suggesting that Sox9 may influence epicardial cell fate decisions. Immunofluorescence analyses revealed defective epicardial attachment and decreased epicardial-derived cell invasion into the ventricular myocardium associated with delayed coronary plexus formation. This study expands our understanding of the role of Sox9 in epicardial biology, demonstrating an important function in regulating epicardial cell invasion, differentiation, and coronary vasculature development. These insights provide a foundation for further investigations into epicardial-mediated mechanisms underlying congenital heart abnormalities.
2025-04-29 | GSE288547 | GEO
Project description:Background: The expression of MDM4, a well-known p53-inhibitor, is positively associated with chemotherapy response and overall survival in epithelial ovarian cancer (EOC). The basis of this association remains elusive. Since the occurrence of metastasis is one of the factors responsible for the high death rate of this cancer, we analyzed MDM4 involvement in EOC metastatic process. Methods: In vivo and in vitro models, based on 2D and 3D assays, were employed to assess the activity of MDM4 in ovarian cancer progression. A 3D-bioprinting co-culture system was ad hoc developed for this study. Proteomic analysis was conducted on 3D multicellular tumour spheroids to assess pathways triggered by MDM4 overexpression. Results: In mouse models, increased MDM4 reduced intraperitoneal dissemination of human and murine EOC cells, independently of p53 and in a cell-autonomous way. Consistently, high MDM4 correlates with increased overall survival probability in large public data sets. 2D and 3D assays indicated that MDM4 impairs the early steps of the metastatic process. The 3D-bioprinting co-culture system showed reduced dissemination and intravasation into vessel-like structures of MDM4-expressing cells. Proteomic analysis of EOC spheroids revealed that MDM4 reduces protein synthesis and decreases mTOR signaling. Accordingly, MDM4 did not further inhibit EOC cell migration when its activity towards mTOR is blocked genetically or pharmacologically. Conversely, increased MDM4 reduced the efficacy of mTOR inhibitors in constraining EOC cell migration. Conclusions: Overall, these data clarify the antagonism of MDM4 towards EOC progression and suggest the usefulness of MDM4 assessment for tailored application of mTOR targeted therapy.
2021-05-27 | PXD019935 | Pride