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A genomic enhancer signature associates with Hepatocellular Carcinoma prognosis

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212342 | GEO | 2022/09/02

REPOSITORIES: GEO

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Genome-wide chromatin loop landscape in HCC

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.

2022-09-01 | GSE212055 | GEO

Long non-coding RNAs and mRNAs profiles in mouse liver development

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Long non-coding RNAs and mRNAs profiles in mouse liver development

2014-05-20 | E-GEOD-57824 | biostudies-arrayexpress

RNAseq analysis of genes differentially expressed in SMMC7721 cells with SNRPE knockdown

Project description:Hepatocellular carcinoma (HCC) is a malignant tumor with poor prognosis and lack of effective treatment targets is the major challenge in treating HCC. Previous studies have revealed significant changes in spliceosome-related genes in HCC. The unique expression pattern in tumor cells makes oncofetal proteins ideal candidate targets for cancer diagnosis and treatment. Therefore, we focused on the differentially expressed splicing factors in embryonic liver development and HCC. We identified an oncofetal splicing factor, small nuclear ribonucleoprotein polypeptide E (SNPRE).In order to better understand the effect of SNRPE in HCC, we knocked down SNRPE using siRNA (siSNRPE) assessed the gene expression pattern by RNA-Seq.

2023-09-01 | GSE197092 | GEO

VL30 retro-transposons are TRIM24-repressed enhancers that generate non-coding RNA to regulate gene expression in mouse hepatocytes. [ChIP-Seq]

Project description:TRIM24 and TRIM33 interact to form a corepressor complex that suppresses murine hepatocellular carcinoma (HCC). TRIM24 and TRIM33 cooperatively repress retinoic acid receptor dependent activity of VL30 retro-transposons in hepatocytes in vivo. In TRIM24 knockout hepatocytes, VL30 long terminal repeats (LTRs) generate enhancer (e)RNAs and act as surrogate promoter and enhancer elements deregulating expression of neighbouring genes. We show that a VL30 LTR-derived eRNA is essential to activate the lipocalin 13 gene in hepatocytes in vivo. A further consequence of VL30 de-repression is the accumulation of retro-transcribed VL30 DNA in the cytoplasm of TRIM24-mutant hepatocytes and activation of the viral defence/interferon response. VL30 activation therefore modulates gene expression via the enhancer activity of the LTRs and by activation of the interferon response. Both of these processes are genetically linked to HCC development suggesting that VL30 repression by TRIM24 plays an important role in tumour suppression. Examination of H3k4me3 and RNA pol II in liver by deep sequencing.

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A novel role of stem cell factor SALL4 as an oncofetal protein in hepatocellular carcinoma

Project description:Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Treatment of HCC remains abysmal; discovery of novel pathways implicated in hepatocarcinogenesis is needed for more effective therapeutics. SALL4 is a stem cell factor essential for the maintenance of embryonic stem cell self-renewal properties and expressed in fetal liver, but silenced in normal adult liver. We observed that expression of SALL4 in murine liver in a transgenic model led to development of HCC. In humans, SALL4 is re-expressed as an oncofetal protein in a subgroup of HCC patients with unfavorable prognoses. Loss-of-function studies demonstrated that SALL4 is essential for human HCC cell survival and tumorigenicity. We demonstrated that a peptide can block the oncogenic function of SALL4 in HCC by modulating the PTEN/AKT pathway. Our findings reveal a novel role of SALL4 in HCC with important implications for understanding disease mechanisms and development of innovative therapeutics. Cultured cells from HCC cell line SNU-398 with scrambled or SALL4 shRNA knockdown were used for RNA extraction and hybridization on Affymetrix microarrays.

2012-02-22 | E-GEOD-35965 | biostudies-arrayexpress

VL30 retro-transposons are TRIM24-repressed enhancers that generate non-coding RNA to regulate gene expression in mouse hepatocytes. [RNA-Seq]

Project description:TRIM24 and TRIM33 interact to form a corepressor complex that suppresses murine hepatocellular carcinoma (HCC). TRIM24 and TRIM33 cooperatively repress retinoic acid receptor dependent activity of VL30 retro-transposons in hepatocytes in vivo. In TRIM24 knockout hepatocytes, VL30 long terminal repeats (LTRs) generate enhancer (e)RNAs and act as surrogate promoter and enhancer elements deregulating expression of neighbouring genes. We show that a VL30 LTR-derived eRNA is essential to activate the lipocalin 13 gene in hepatocytes in vivo. A further consequence of VL30 de-repression is the accumulation of retro-transcribed VL30 DNA in the cytoplasm of TRIM24-mutant hepatocytes and activation of the viral defence/interferon response. VL30 activation therefore modulates gene expression via the enhancer activity of the LTRs and by activation of the interferon response. Both of these processes are genetically linked to HCC development suggesting that VL30 repression by TRIM24 plays an important role in tumour suppression. RNA profiles in liver of wild type (WT) and Trim24-/- mice by deep sequencing using Illumina GAIIx.

2013-01-01 | E-GEOD-39851 | biostudies-arrayexpress

HCC Gene Expression Profile

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2022-05-04 | E-MTAB-7189 | biostudies-arrayexpress

PC4-mediated Ku PARylation facilitates NHEJ-dependent DNA damage repair

Project description:Radiotherapy is one of the mainstays for the treatment of hepatocellular carcinoma (HCC); however, a substantial fraction of HCC patients develops radioresistance and eventually suffer from tumour progression or relapse, a major impediment to the use of radiotherapy. One of the main goals in HCC management is to elucidate the mechanisms underlying radioresistance and identify novel therapeutic targets to improve the patients' prognosis. In this study, we report a DNA repair enhancer, human positive cofactor 4 (PC4), that promotes NHEJ-based DNA repair and renders HCC cells resistant to radiation. Mechanistically, PC4 interacts with PARP1 and directs Ku complex PARylation, resulting in successful recruitment of the Ku complex to damaged chromatin and increasing the efficiency of NHEJ repair. Clinically, PC4 is highly expressed in tumour tissues, which is correlated with poor prognosis in HCC patients. Taken together, our data suggest that PC4 is a DNA repair driver that can be targeted to radiosensitize HCC.

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