TY  - JOUR
A1  - Court, Franck
A1  - Le Boiteux, Elisa
A1  - Fogli, Anne
A1  - Müller-Barthélémy, Mélanie
A1  - Vaurs-Barrière, Catherine
A1  - Chautard, Emmanuel
A1  - Pereira, Bruno
A1  - Biau, Julian
A1  - Kemeny, Jean-Louis
A1  - Khalil, Toufic
A1  - Karayan-Tapon, Lucie
A1  - Verrelle, Pierre
A1  - Arnaud, Philippe
T1  - Transcriptional alterations in glioma result primarily from DNA methylation–independent mechanisms
Y1  - 2019/10/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 1605 
EP  - 1621 
DO  - 10.1101/gr.249219.119 
VL  - 29 
IS  - 10 
UR  - http://genome.cshlp.org/content/29/10/1605.abstract 
N2  - In cancer cells, aberrant DNA methylation is commonly associated with transcriptional alterations, including silencing of tumor suppressor genes. However, multiple epigenetic mechanisms, including polycomb repressive marks, contribute to gene deregulation in cancer. To dissect the relative contribution of DNA methylation–dependent and –independent mechanisms to transcriptional alterations at CpG island/promoter-associated genes in cancer, we studied 70 samples of adult glioma, a widespread type of brain tumor, classified according to their isocitrate dehydrogenase (IDH1) mutation status. We found that most transcriptional alterations in tumor samples were DNA methylation–independent. Instead, altered histone H3 trimethylation at lysine 27 (H3K27me3) was the predominant molecular defect at deregulated genes. Our results also suggest that the presence of a bivalent chromatin signature at CpG island promoters in stem cells predisposes not only 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. Highly expressed genes were more likely to be repressed by H3K27me3 than by DNA methylation. Our findings support a model in which altered 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. Our study provides the first comprehensive description of epigenetic changes in glioma and their relative contribution to transcriptional changes. It may be useful for the design of drugs targeting cancer-related epigenetic defects. 
ER  -