Researchers have identified a new epigenetic reprogramming mechanism ensuring increased dosage of an “oncogene module”.

Changes in the DNA methylation status reshape the gene expression repertoire in cancer. Combining DNA methylation and expression profiles from hepatocellular carcinoma, using both a mouse model and human samples, we report an epigenetic reprogramming process that ensures increased dosage of an “oncogene module”.

Hypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer

Summary. Epigenetic modifications such as aberrant DNA methylation reshape the gene expression repertoire in cancer. Here, we used a clinically relevant hepatocellular carcinoma (HCC) mouse model (Alb-R26Met) to explore the impact of DNA methylation on transcriptional switches associated with tumorigenesis. We identified a striking enrichment in genes simultaneously hypermethylated in CpG islands (CGIs) and overexpressed. These hypermethylated CGIs are located either in the 5’-UTR or in the gene body region. Remarkably, such CGI hypermethylation accompanied by gene upregulation also occurs in 56% of HCC patients, which belong to the “HCC proliferative-progenitor” subclass. Most of the genes hypermethylated in CGIs and upregulated in the Alb-R26Met cancer model are also hypermethylated in CGIs and upregulated in a large proportion of HCC patients. Among reprogrammed genes, several are well-known oncogenes. For others not previously linked to cancer, we demonstrate here their action together as an “oncogene module”. Thus, hypermethylation of gene body CGIs is predictive of elevated oncogene levels in cancer, offering a novel stratification strategy, and perspectives to normalise cancer gene dosages.

Maina-Nature-communications

TOP: The scheme illustrates the overall strategy employed in this study. DNA methylation and gene expression levels were analysed in a clinically relevant hepatocellular carcinoma (HCC) mouse model generated in Maina Team (Alb-R26Met) and in control livers. Outcomes were compared with HCC human databases. A set of oncogenes were then functionally validated using a range of assays both in vitro and in vivo.
BOTTOM: The scheme summarizes the outcomes. In healthy cells, certain oncogenes, although with their promoter in an active state, are not expressed. In contrast, in cancer cells, CGI hypermethylation in the gene body leads to the expression of the oncogenes.

To know more :
  • Hypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer

    Maria Arechederra1, Fabrice Daian1, Annie Yim2, Sehrish Khan Bazai1, Sylvie Richelme1, Rosanna Dono1, Andrew J. Saurin1, Bianca H. Habermann1, and Flavio Maina1,*

    1 Aix Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), Parc Scientifique de Luminy, Marseille (France)

    2 Computational Biology Group, Max Planck Institute of Biochemistry, Martinsried (Germany)

    Nature Communications 2018 Aug 8;9(1):3164. doi: 10.1038/s41467-018-05550-5.

  • More information here
Contact :

Flavio Maina – flavio.maina@univ-amu.fr