Most of the deregulated CpG-island-controlled genes in glioma do not show DNA methylation defects

Arnaud, P.; Court, F.; Le Boiteux, E.; Fogli, A.; Müller-Barthelemy, M.; Vaurs-Barriere, C.; Chautard, E.; Pereira, B.; Biau, J.; Kemeny, J.-L.; Khalil, T.; Karayan-Tapon, L.; Verrelle, P.

doi:10.1101/516997

bioRxiv · 10.1101/516997

Most of the deregulated CpG-island-controlled genes in glioma do not show DNA methylation defects

Arnaud, P.·Court, F.·Le Boiteux, E.·Fogli, A.·Müller-Barthelemy, M.·Vaurs-Barriere, C.·Chautard, E.·Pereira, B.·Biau, J.·Kemeny, J.-L.·Khalil, T.·Karayan-Tapon, L.·Verrelle, P.

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Abstract

BackgroundAberrant DNA methylation is a cancer cell feature that is commonly associated with transcriptional alterations. However, the primary role of this defect in the genome-wide cancer-associated gene deregulation is not clear. Here, we evaluated the relative contribution of DNA methylation-dependent and -independent mechanisms to transcriptional alterations at CpG-island/promoter-associated genes in samples of adult glioma, a widespread type of brain tumor. ResultsExtensive molecular analyses of glioma samples with wild type IDH (IDHwt) and mutated IDH (IDHmut) found DNA hypermethylation only in a minority of genes showing loss or gain of expression. Specifically, in IDHwt samples, more than 75% of aberrantly repressed genes did not display DNA methylation defects at their CpG-island promoter. Conversely, altered H3K27me3 was the predominant molecular defect at deregulated genes. Moreover, the presence of a bivalent chromatin signature at CpG-island promoters in stem cells might not only predispose to hypermethylation, as widely documented, but more generally to all types of transcriptional alterations in transformed cells. In addition, the gene expression strength in healthy brain cells influences the choice between DNA methylation- and H3K27me3-associated silencing in glioma. Our findings support a model whereby the altered control of H3K27me3 dynamics, more specifically defects in the interplay between polycomb protein complexes and the brain-specific transcriptional machinery, is the main cause of transcriptional alteration in glioma cells. ConclusionsOur study provides a comprehensive and updated description of the epigenetic deregulations in glioma that could be useful for the design of drugs to target cancer-related epigenetic defects.

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Arnaud, P., Court, F., Le Boiteux, E., Fogli, A., Müller-Barthelemy, M., Vaurs-Barriere, C., Chautard, E., Pereira, B., Biau, J., Kemeny, J.-L., Khalil, T., Karayan-Tapon, L., Verrelle, P.. 2019-01-11. Most of the deregulated CpG-island-controlled genes in glioma do not show DNA methylation defects. https://doi.org/10.1101/516997

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