Oncometabolite 2-hydroxygluterate regulates gene expression through preferential inhibition of specific histone demethylases

In several types of cancer but also in some cases of 2-hydroxyglutaric aciduria, a gain of function mutation in the IDH enzymes leads to the accumulation of 2-hydroxyglutarate. The oncometabolite 2-hydroxyglutarate has been identified as inhibitor of TET and JmjC-domain containing histone demethylases due to its structural similarities with a-KG, the required co-factor for these demethylases. Accumulation of 2-hydroxyglutarate can lead to changes in DNA and histone methylation contributing to the initiation and progression of cancer. The effects of 2-hydroxyglutarate on repressive histone markers such as histone H3 lysine 27 and histone H3 lysine 9 methylation have been highlighted in several studies although the effects on markers of open chromatin such histone H3 lysine 36 and histone H3 lysine 4 methylation remain unclear. Additionally, in studies investigating the effects of 2-hydroxyglutarate, it has been difficult to distinguish if the pathological effects are attributed to DNA or histone methylation changes. Saccharomyces cerevisiae could serve as a model organism to study the effects of 2-hydroxyglutarate specifically on histone markers as this model is devoid of DNA methylation.
In this study we show that elevated 2-hydroxyglutarate levels in S. cerevisiae can lead to genetic background-dependent gene expression changes that are accompanied by altered H3K4 and H3K36 methylation only at specific and often unrelated loci. By working with histone demethylase knockouts strains we show that while inhibition of all of the H3K4 and H3K36 demethylase contributes to the observed methylation changes, only the preferential inhibition of Rph1 is sufficient to induce extensive gene expression changes. These results provide novel insights into genome-wide effects of 2-hydroxyglutarate and highlight Rph1, the yeast homolog of KDM4 demethylases, as its preferential demethylase target.