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: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: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.
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