2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition

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...

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Autores principales: Gavriil, Marios, Proietto, Marco, Paczia, Nicole, Ginolhac, Aurelien, Halder, Rashi, Valceschini, Elena, Sauter, Thomas, Linster, Carole L, Sinkkonen, Lasse
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10681907/
https://www.ncbi.nlm.nih.gov/pubmed/38011998
http://dx.doi.org/10.26508/lsa.202302333
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author Gavriil, Marios
Proietto, Marco
Paczia, Nicole
Ginolhac, Aurelien
Halder, Rashi
Valceschini, Elena
Sauter, Thomas
Linster, Carole L
Sinkkonen, Lasse
author_facet Gavriil, Marios
Proietto, Marco
Paczia, Nicole
Ginolhac, Aurelien
Halder, Rashi
Valceschini, Elena
Sauter, Thomas
Linster, Carole L
Sinkkonen, Lasse
author_sort Gavriil, Marios
collection PubMed
description 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.
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spelling pubmed-106819072023-11-30 2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition Gavriil, Marios Proietto, Marco Paczia, Nicole Ginolhac, Aurelien Halder, Rashi Valceschini, Elena Sauter, Thomas Linster, Carole L Sinkkonen, Lasse Life Sci Alliance Research Articles 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. Life Science Alliance LLC 2023-11-27 /pmc/articles/PMC10681907/ /pubmed/38011998 http://dx.doi.org/10.26508/lsa.202302333 Text en © 2023 Gavriil et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Gavriil, Marios
Proietto, Marco
Paczia, Nicole
Ginolhac, Aurelien
Halder, Rashi
Valceschini, Elena
Sauter, Thomas
Linster, Carole L
Sinkkonen, Lasse
2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition
title 2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition
title_full 2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition
title_fullStr 2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition
title_full_unstemmed 2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition
title_short 2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition
title_sort 2-hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via rph1 inhibition
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10681907/
https://www.ncbi.nlm.nih.gov/pubmed/38011998
http://dx.doi.org/10.26508/lsa.202302333
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