RT Journal Article SR Electronic T1 2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202302333 DO 10.26508/lsa.202302333 VO 7 IS 2 A1 Gavriil, Marios A1 Proietto, Marco A1 Paczia, Nicole A1 Ginolhac, Aurelien A1 Halder, Rashi A1 Valceschini, Elena A1 Sauter, Thomas A1 Linster, Carole L A1 Sinkkonen, Lasse YR 2024 UL https://www.life-science-alliance.org/content/7/2/e202302333.abstract AB 2-Hydroxyglutarate (2-HG) is an oncometabolite that accumulates in certain cancers. Gain-of-function mutations in isocitrate dehydrogenase lead to 2-HG accumulation at the expense of alpha-ketoglutarate. Elevated 2-HG levels inhibit histone and DNA demethylases, causing chromatin structure and gene regulation changes with tumorigenic consequences. We investigated the effects of elevated 2-HG levels in Saccharomyces cerevisiae, a yeast devoid of DNA methylation and heterochromatin-associated histone methylation. Our results demonstrate genetic background-dependent gene expression changes and altered H3K4 and H3K36 methylation at specific loci. Analysis of histone demethylase deletion strains indicated that 2-HG inhibits Rph1 sufficiently to induce extensive gene expression changes. Rph1 is the yeast homolog of human KDM4 demethylases and, among the yeast histone demethylases, was the most sensitive to the inhibitory effect of 2-HG in vitro. Interestingly, Rph1 deficiency favors gene repression and leads to further down-regulation of already silenced genes marked by low H3K4 and H3K36 trimethylation, but abundant in H3K36 dimethylation. Our results provide novel insights into the genome-wide effects of 2-HG and highlight Rph1 as its preferential demethylase target.