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Aberrant enhancer reprogramming drives hepatic carcinogenesis through global transcriptional reprogramming [ChIP-seq]

ABSTRACT: Aberrant enhancer reprogramming drives hepatic carcinogenesis through global transcriptional reprogramming [ChIP-seq]

PROVIDER: PRJNA507538 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8260213_1.fastq.gz	Fastqsanger.gz
	SRR8260213_2.fastq.gz	Fastqsanger.gz
	SRR8260214_1.fastq.gz	Fastqsanger.gz
	SRR8260214_2.fastq.gz	Fastqsanger.gz
	SRR8260215_1.fastq.gz	Fastqsanger.gz

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Aberrant enhancer reprogramming drives hepatic carcinogenesis through global transcriptional reprogramming

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Epigenetic reprogramming in hepatic carcinogenesis

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Aberrant enhancer reprogramming drives hepatic carcinogenesis through global transcriptional reprogramming [RNA-seq]

Project description:Hepatocellular carcinomas (HCC) exhibit distinct promoter hypermethylation patterns, but the epigenetic regulation and function of transcriptional enhancers remain unclear. Here, our affinity- and bisulfite-based whole-genome sequencing analyses reveal global enhancer hypomethylation in human HCCs. Integrative epigenomic characterization further pinpoints a recurrent hypomethylated enhancer of CCAAT/enhancer-binding protein-beta (C/EBPβ) which correlates with C/EBPβ over-expression and poorer prognosis of patients. Demethylation of C/EBPβ enhancer reactivates a self-reinforcing enhancer-target loop via direct transcriptional up-regulation of enhancer RNA. Conversely, deletion of this enhancer via CRISPR/Cas9 reduces C/EBPβ expression and its genome-wide co-occupancy with BRD4 at H3K27ac-marked enhancers and super-enhancers, leading to drastic suppression of driver oncogenes and abrogation of HCC tumorigenicity. Hepatitis B X protein transgenic mouse model of HCC recapitulates this paradigm, as C/ebpβ enhancer hypomethylation associates with oncogenic activation in early tumorigenesis. These results support a causal link between aberrant enhancer hypomethylation and C/EBPβ over-expression, thereby driving hepatocarcinogenesis through global transcriptional reprogramming.

2019-01-06 | GSE123098 | GEO

Aberrant enhancer reprogramming drives hepatic carcinogenesis through global transcriptional reprogramming [ChIP-seq]

2019-01-06 | GSE123097 | GEO

Aberrant enhancer reprogramming drives hepatic carcinogenesis through global transcriptional reprogramming

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-01-06 | GSE123099 | GEO

Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming.

Project description:Hepatocellular carcinomas (HCC) exhibit distinct promoter hypermethylation patterns, but the epigenetic regulation and function of transcriptional enhancers remain unclear. Here, our affinity- and bisulfite-based whole-genome sequencing analyses reveal global enhancer hypomethylation in human HCCs. Integrative epigenomic characterization further pinpoints a recurrent hypomethylated enhancer of CCAAT/enhancer-binding protein-beta (C/EBPβ) which correlates with C/EBPβ over-expression and poorer prognosis of patients. Demethylation of C/EBPβ enhancer reactivates a self-reinforcing enhancer-target loop via direct transcriptional up-regulation of enhancer RNA. Conversely, deletion of this enhancer via CRISPR/Cas9 reduces C/EBPβ expression and its genome-wide co-occupancy with BRD4 at H3K27ac-marked enhancers and super-enhancers, leading to drastic suppression of driver oncogenes and HCC tumorigenicity. Hepatitis B X protein transgenic mouse model of HCC recapitulates this paradigm, as C/ebpβ enhancer hypomethylation associates with oncogenic activation in early tumorigenesis. These results support a causal link between aberrant enhancer hypomethylation and C/EBPβ over-expression, thereby contributing to hepatocarcinogenesis through global transcriptional reprogramming.

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Loss of tumor suppressor IGFBP4 drives epigenetic reprogramming in hepatic carcinogenesis.

Project description:Genomic sequencing of hepatocellular carcinoma (HCC) uncovers a paucity of actionable mutations, underscoring the necessity to exploit epigenetic vulnerabilities for therapeutics. In HCC, EZH2-mediated H3K27me3 represents a major oncogenic chromatin modification, but how it modulates the therapeutic vulnerability of signaling pathways remains unknown. Here, we show EZH2 acts antagonistically to AKT signaling in maintaining H3K27 methylome through epigenetic silencing of IGFBP4. ChIP-seq revealed enrichment of Ezh2/H3K27me3 at silenced loci in HBx-transgenic mouse-derived HCCs, including Igfbp4 whose down-regulation significantly correlated with EZH2 overexpression and poor survivals of HCC patients. Functional characterizations demonstrated potent growth- and invasion-suppressive functions of IGFBP4, which was associated with transcriptomic alterations leading to deregulation of multiple signaling pathways. Mechanistically, IGFBP4 stimulated AKT/EZH2 phosphorylation to abrogate H3K27me3-mediated silencing, forming a reciprocal feedback loop that suppressed core transcription factor networks (FOXA1/HNF1A/HNF4A/KLF9/NR1H4) for normal liver homeostasis. Consequently, the in vivo tumorigenicity of IGFBP4-silenced HCC cells was vulnerable to pharmacological inhibition of EZH2, but not AKT. Our study unveils chromatin regulation of a novel liver tumor suppressor IGFBP4, which constitutes an AKT-EZH2 reciprocal loop in driving H3K27me3-mediated epigenetic reprogramming. Defining the aberrant chromatin landscape of HCC sheds light into the mechanistic basis of effective EZH2-targeted inhibition.

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Hepatic expression data from 2-stage carcinogenesis study in rats

Project description:Hepatic gene expression profiles in 2-stage carcinogenesis study were analyzed with comprehensive DNA methylation data. Combined analysis suggested that PTEN signaling and immune response such as antigen presentation was related to one side of early heapatocarcinogenesis. We used microarrays to obtain the global gene expression profile of livers to understand the mechanism of carcinogenesis.

2016-10-24 | GSE51797 | GEO

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