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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.
This article was published in the following journal.
Name: Nature communications
Cholangiocarcinoma is a lethal biliary cancer, with an unclear molecular pathogenesis. Alternative splicing is a post-transcriptional modification that generates mature mRNAs, which are subsequently t...
Hepatic arterial infusion pumps are increasingly utilized as an option for liver directed therapy in the treatment of metastatic colorectal carcinoma. After skeletonization of the hepatic artery throu...
Reactivation of interspersed repetitive sequences due to loss of methylation is associated with genomic instability, one of the hallmarks of cancer cells. LINE-1 hypomethylation is a surrogate marker ...
The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative transdiffer...
As the second most common malignant bone tumor in children and adolescents, Ewing sarcoma is initiated and exacerbated by a chimeric oncoprotein, most commonly, EWS-FLI1. In this study, we apply epige...
Hypothesis: (1) Aripiprazole treatment will be superior to placebo in reducing aggression and irritability in autistic individuals as shown by reductions in the Aberrant Behavior Checklist...
The purpose of this study is to determine the effectiveness of curcumin in reducing the number of aberrant crypt foci (ACF) in the colon.
The investigators hypothesize that aberrant hypermethylation of tumour suppressor genes is an important mechanism for Epstein-Barr Virus (EBV) - related gastric carcinogenesis, the promote...
Over the past ten years, the number of endovascular procedures has increased by 5% per year in Europe with the development of interventional cardiology, such as percutaneous coronary angio...
This is a Phase 1, single-centre, open-label, parallel-group study in subjects with moderate hepatic impairment and subjects with normal hepatic function. Child-Pugh (CP) scoring will be u...
Increase in the temperature of the atmosphere near the Earth's surface and in the troposphere, which can contribute to changes in global climate patterns.
The origin, production or development of cancer through genotypic and phenotypic changes which upset the normal balance between cell proliferation and cell death. Carcinogenesis generally requires a constellation of steps, which may occur quickly or over a period of many years.
A dioxygenase that repairs alkylated DNA and RNA by oxidative demethylation. It has highest activity towards single-stranded RNA containing 3-methyluracil, followed by SINGLE-STRANDED DNA containing 3-methylthymine and specifically demethylates N(6)-methyladenosine (m6A) RNA, the most common internal modification of MESSENGER RNA (mRNA) in higher EUKARYOTES. It contributes to the regulation of the global metabolic rate, energy HOMEOSTASIS, as well as body fat accumulation by regulating the differentiation of ADIPOCYTES into BROWN FAT CELLS or WHITE FAT CELLS.
A CCAAT-enhancer-binding protein found in LIVER; ADIPOSE TISSUE; INTESTINES; LUNG; ADRENAL GLANDS; PLACENTA; OVARY and peripheral blood mononuclear cells (LEUKOCYTES, MONONUCLEAR). Experiments with knock-out mice have demonstrated that CCAAT-enhancer binding protein-alpha is essential for the functioning and differentiation of HEPATOCYTES and ADIPOCYTES.
Mice selectively bred for hypersusceptibility to two-stage chemical skin carcinogenesis. They are also hypersusceptible to UV radiation tumorigenesis with single high-dose, but not chronic low-dose, exposures. SENCAR (SENsitive to CARcinogenesis) mice are used in research as an animal model for tumor production.
Hepatology is the study of liver, gallbladder, biliary tree, and pancreas, and diseases associated with them. This includes viral hepatitis, alcohol damage, cirrhosis and cancer. As modern lifestyles change, with alcoholism and cancer becoming more promi...
The development and maintenance of an organism is orchestrated by a set of chemical reactions that switch parts of the genome off and on at strategic times and locations. Epigenetics is the study of these reactions and the factors that influence them. ...