RNAseq analysis of genes differentially expressed in SMMC7721 cells with SNRPE knockdown
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE197092 | GEO | 2023/09/01
REPOSITORIES: GEO
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Project description:Understanding the roles of splicing factors and splicing events during tumorigenesis would open new avenues for targeted therapies. Here we identify an oncofetal splicing factor, heterogeneous nuclear ribonucleoprotein M (HNRNPM), which promotes tumorigenesis and predicts poor prognosis of hepatocellular carcinoma (HCC) patients. HNRNPM knockdown almost completely abolishes HCC tumorigenesis. Transcriptomic analysis combined with RNA-immunoprecipatation sequencing revealed that HNRNPM induces lncRNA-TRIM7-AS exon 2 inclusion. The transcript containing exon 2 binds to coding sequences of TRIM7 mRNA, causes dissociation of translation elongation factors from TRIM7 mRNA, and thereby inhibits TRIM7 mRNA translation. In contrast, the transcript including exon 3 preferentially binds to the 3’ untranslated region of TRIM7 mRNA, protects TRIM7 mRNA from microRNA-145-5p induced degradation, and thereby increases TRIM7 expression. Through inducing exon 2 inclusion, HNRNPM downregulates TRIM7 protein expression, which mediates the pro-tumorigenic roles of HNRNPM. Collectively, these data demonstrate detailed mechanistic links between an oncofetal splicing factor, a splicing event and tumorigenesis, and establish splicing factors and splicing events as potential therapeutic targets.
2022-06-01 | GSE169223 | GEO
Project description:We investigated the genomic enhancer landscape of Hepatocellular Carcinoma (HCC) using H3K27ac ChIP-seq and HiC/HiChIP data from resected tumour samples of 30 patients, whose genome, transcriptome, and clinical trajectory data were available. Differential enhancer analysis revealed dysregulated enhancer loci, but without strong enrichment of underlying DNA mutation hotspots. As many of the gain-in-tumour enhancer associated genes were fetal liver hepatoblast genes, we investigated the stochastic expression pattern of the overlapping genes (epigenetic oncofetal genes) using previously published single cell RNA-seq data, in which the patients partially overlapped. The proportion of cells expressing epigenetic oncofetal genes clustered liver tissue samples into two groups - adjacent normal liver-like, or oncofetal-like. Notably, gain-in-tumour enhancer associated genes showed prognostic value, with patient clusters revealed by co-clustering the differential gene expression pattern. Altogether, we report the genomic enhancer signature that associates with differential prognosis in HCC. Findings that cohere with oncofetal reprogramming in HCC is underpinned by genome-wide enhancer rewiring. Our results present the epigenetic changes in HCC that offer the rational selection of epigenetic-driven gene targets for therapeutic intervention or disease prognostication in HCC.
2022-09-02 | GSE212342 | GEO
Project description:We investigated the genomic enhancer landscape of Hepatocellular Carcinoma (HCC) using H3K27ac ChIP-seq and HiC/HiChIP data from resected tumour samples of 30 patients, whose genome, transcriptome, and clinical trajectory data were available. Differential enhancer analysis revealed dysregulated enhancer loci, but without strong enrichment of underlying DNA mutation hotspots. As many of the gain-in-tumour enhancer associated genes were fetal liver hepatoblast genes, we investigated the stochastic expression pattern of the overlapping genes (epigenetic oncofetal genes) using previously published single cell RNA-seq data, in which the patients partially overlapped. The proportion of cells expressing epigenetic oncofetal genes clustered liver tissue samples into two groups - adjacent normal liver-like, or oncofetal-like. Notably, gain-in-tumour enhancer associated genes showed prognostic value, with patient clusters revealed by co-clustering the differential gene expression pattern. Altogether, we report the genomic enhancer signature that associates with differential prognosis in HCC. Findings that cohere with oncofetal reprogramming in HCC is underpinned by genome-wide enhancer rewiring. Our results present the epigenetic changes in HCC that offer the rational selection of epigenetic-driven gene targets for therapeutic intervention or disease prognostication in HCC.
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Project description:Abnormal alternative splicing (AS) caused by alterations to splicing factors contributes to tumor progression. Nonetheless, the relevant targets and mechanisms remain elusive in hepatocellular carcinoma (HCC). Here, we reported that overexpression of Ubiquitin-specific protease 39 (USP39), a spliceosome component of the U4/U6.U5 tri-snRNP complex, is associated with poor clinical outcomes and proliferative signaling. Functionally, hepatocyte-specific USP39 knockin mice exhibited enhanced hepatocarcinogenesis. In vitro, USP39 promoted HCC cell proliferation and cell cycle progression in a spliceosome-dependent manner. Transcriptomic analysis revealed that USP39 depletion led to comprehensively impaired constitutive splicing and intriguingly, selective AS of hundreds of genes. USP39-mediated splicing switch of KANK2-S to KANK2-L increased the tumorigenic potential of HCC cells through accelerating KANK2 translation. Mechanistically, USP39 modulates exon inclusion/exclusion via interaction with SRSF6 or hnRNPC in a position-dependent manner. These findings highlight a role for USP39 as a splicing regulator in HCC biology and establishing its position-dependent splicing model.
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Project description:Understanding the roles of splicing factors and splicing events during human tumorigenesis would open new avenues for targeted therapeutics. Here we identify an oncofetal splicing factor MBNL3, which indicates poor prognosis, and promotes hepatocellular carcinoma (HCC) tumorigenesis. Genetic MBNL3 inhibition almost completely abolishes HCC tumorigenesis. Transcriptomic analysis revealed that MBNL3 induces PXN antisense transcript 1 exon 4 inclusion. The transcript lacking exon 4 binds to coding sequences of PXN mRNA, causes dissociation of translation elongation factors from PXN mRNA, thereby inhibiting PXN mRNA translation. Whereas the transcript containing exon 4 preferentially binds to 3' untranslated region of PXN mRNA, protects PXN mRNA from microRNA-24-AGO2 complex-induced degradation, thereby increasing PXN expression. Through inducing exon 4 inclusion, MBNL3 upregulates PXN expression, which mediates the pro-tumorigenic roles of MBNL3. Collectively, these data demonstrate detailed mechanistic links between oncofetal splicing factor, splicing event, and tumorigenesis, and establish splicing factors and splicing events would be potential therapeutic targets.
2017-03-08 | GSE95778 | GEO
Project description:Many protein-coding oncofetal genes are highly expressed in murine and human fetal liver and silenced in adult liver. The protein products of these hepatic oncofetal genes have been used as clinical markers for the recurrence of hepatocellular carcinoma (HCC) and as therapeutic targets for HCC. Herein, we examined the expression profiles of long non-coding RNAs (lncRNAs) and mRNAs found in fetal and adult liver in mice.LncRNA-mPvt1 is an oncofetal RNA that was found to promote cell proliferation, cell cycling and the expression of stem cell-like properties of murine cells. Human lncRNA-hPVT1 promotes cell proliferation, cell cycling and the acquisition of stem cell-like properties in HCC cells by stabilizing NOP2 protein. Regulation of the lncRNA-hPVT1/NOP2 pathway may have beneficial effects in the treatment of HCC. We collected mouse fetal livers (E12.5, E14.5, E17.5 days), neonatal murine livers and adult murine livers (8 weeks). The total RNAs recovered from these developmental livers and were used to acquire different expression profiles of mRNAs and lncRNAs.
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Project description:Many protein-coding oncofetal genes are highly expressed in murine and human fetal liver and silenced in adult liver. The protein products of these hepatic oncofetal genes have been used as clinical markers for the recurrence of hepatocellular carcinoma (HCC) and as therapeutic targets for HCC. Herein, we examined the expression profiles of long non-coding RNAs (lncRNAs) and mRNAs found in fetal and adult liver in mice.LncRNA-mPvt1 is an oncofetal RNA that was found to promote cell proliferation, cell cycling and the expression of stem cell-like properties of murine cells. Human lncRNA-hPVT1 promotes cell proliferation, cell cycling and the acquisition of stem cell-like properties in HCC cells by stabilizing NOP2 protein. Regulation of the lncRNA-hPVT1/NOP2 pathway may have beneficial effects in the treatment of HCC.
2014-05-20 | GSE57824 | GEO
Project description:The investigation of spliceosomal processes is currently a topic of intense research in molecular biology. In the molecular mechanism of alternative splicing, a multi-protein–RNA complex – the spliceosome – plays a crucial role. To understand the biological processes of alternative splicing, it is essential to comprehend the biogenesis of the spliceosome.
In this paper, we propose the first abstract model of the regulatory assembly pathway of the human spliceosomal subunit U1. Using Petri nets, we describe its highly ordered assembly that takes place in a stepwise manner.
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Project description:The spliceosome is a multimolecular ribonucleoprotein complex, which catalyzes the removal of introns from pre-mRNA and extends the complexity of genetic information by defining alternative transcripts. Here we analyzed the in vivo function of CD2BP2, which is a marker of early spliceosomal complexes. Using gene targeting in mice, we show that constitutive or mesoderm- specific ablation of the CD2BP2 gene causes embryonic lethality by E10.5 associated with delayed development, growth retardation and pericard effusion. Transcriptome analysis in CD2BP2 deficient bone-marrow-derived macrophages (BMM) and podocytes revealed dramatic alterations in the alternative splicing pattern of several mRNAs including VEGFA. Consistent with a previously described critical role of specific VEGFA isoforms for podocyte integrity, mice, which specifically lack CD2BP2flox/flox in this cell type, develop progressive albuminuria followed by lethal kidney failure. We further identified the phosphatase PP1 as a GYF domain independent CD2BP2 interaction partner, suggesting that CD2BP2 acts as an important modulator for spliceosome dephosphorylation, thereby affecting alternative splicing of physiologically highly relevant transcripts.
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Project description:Alternative splicing (AS) can produce multiple transcripts with different exon-intron structures from a single pre-mRNA. Pre-mRNA splicing is catalyzed by a dynamic macromolecular ribonucleoprotein (RNP) complex termed the spliceosome. The spliceosome consists of several small nuclear ribonucleoproteins (snRNPs) that bind uridine-rich small nuclear RNA (snRNA). In U1, U2, U4 and U5 snRNPs, snRNA interacts with the conserved Smith antigen (Sm) proteins via a bipartite Sm sequence motif. In eukaryotes, seven Sm proteins (B, D1/2/3, E, F and G) form a heptameric ring-shaped complex surrounding the snRNA. Here, we performed a tandem affinity purification using SMEB as a bait in Arabidopsis cell suspension cultures. At least 45 known/hypothesized and potential novel spliceosome components were identified in Arabidopsis.
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