دورية أكاديمية
2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition.
العنوان: | 2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition. |
---|---|
المؤلفون: | Gavriil M; https://ror.org/036x5ad56 Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg., Proietto M; https://ror.org/036x5ad56 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg., Paczia N; https://ror.org/036x5ad56 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg., Ginolhac A; https://ror.org/036x5ad56 Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg., Halder R; https://ror.org/036x5ad56 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg., Valceschini E; https://ror.org/036x5ad56 Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg., Sauter T; https://ror.org/036x5ad56 Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg., Linster CL; https://ror.org/036x5ad56 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg carole.linster@uni.lu., Sinkkonen L; https://ror.org/036x5ad56 Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg lasse.sinkkonen@uni.lu. |
المصدر: | Life science alliance [Life Sci Alliance] 2023 Nov 27; Vol. 7 (2). Date of Electronic Publication: 2023 Nov 27 (Print Publication: 2024). |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Life Science Alliance, LLC Country of Publication: United States NLM ID: 101728869 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 2575-1077 (Electronic) Linking ISSN: 25751077 NLM ISO Abbreviation: Life Sci Alliance Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: [Woodbury, NY] : Life Science Alliance, LLC, [2018]- |
مواضيع طبية MeSH: | Histone Demethylases*/genetics , Histone Demethylases*/metabolism , Saccharomyces cerevisiae*/genetics , Saccharomyces cerevisiae*/metabolism , Saccharomyces cerevisiae Proteins*/genetics , Saccharomyces cerevisiae Proteins*/metabolism, Gene Expression ; Histones/metabolism ; Methylation |
مستخلص: | 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. (© 2023 Gavriil et al.) |
References: | Cell. 2005 Nov 18;123(4):581-92. (PMID: 16286007) Genome Biol. 2014;15(12):550. (PMID: 25516281) Bioinformatics. 2019 Jun 1;35(12):2084-2092. (PMID: 30395178) EMBO Rep. 2011 May;12(5):463-9. (PMID: 21460794) Nucleic Acids Res. 2019 May 7;47(8):e47. (PMID: 30783653) Genome Biol. 2008;9(9):R137. (PMID: 18798982) Nat Rev Neurol. 2019 Jul;15(7):405-417. (PMID: 31227792) Cell. 2005 Nov 18;123(4):593-605. (PMID: 16286008) Anal Biochem. 2012 Jan 1;420(1):48-53. (PMID: 21925481) Cells. 2021 Sep 07;10(9):. (PMID: 34571995) Nucleic Acids Res. 2015 Jan;43(1):115-28. (PMID: 25477386) Cold Spring Harb Perspect Biol. 2015 Sep 01;7(9):a025064. (PMID: 26330523) Mol Syst Biol. 2012 Jul 17;8:593. (PMID: 22806141) J Biol Chem. 2016 Mar 18;291(12):6036-58. (PMID: 26774271) Nucleic Acids Res. 2007;35(21):e147. (PMID: 18003660) Bioinformatics. 2010 Sep 1;26(17):2204-7. (PMID: 20639541) BMC Res Notes. 2016 Feb 12;9:88. (PMID: 26868221) Nat Commun. 2018 Jan 15;9(1):189. (PMID: 29335486) Nature. 2012 Jan 04;481(7381):389-93. (PMID: 22217937) Nature. 2016 Jan 7;529(7584):110-4. (PMID: 26700815) Nat Chem Biol. 2009 Aug;5(8):593-9. (PMID: 19561621) Nature. 2020 Jun;582(7813):586-591. (PMID: 32494005) J Biol Chem. 2007 May 11;282(19):14262-71. (PMID: 17369256) Nat Rev Clin Oncol. 2021 Oct;18(10):645-661. (PMID: 34131315) Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):E1158-E1167. (PMID: 28154131) Trends Biochem Sci. 2020 Sep;45(9):731-747. (PMID: 32387193) Nat Protoc. 2014 May;9(5):1056-82. (PMID: 24722405) Elife. 2017 Mar 27;6:. (PMID: 28346139) J Biol Chem. 2021 Aug;297(2):100939. (PMID: 34224729) Proc Natl Acad Sci U S A. 2019 Jun 25;116(26):12851-12856. (PMID: 31182575) Nat Commun. 2016 Jun 21;7:11949. (PMID: 27325136) EMBO J. 2004 Jan 28;23(2):354-64. (PMID: 14739930) Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886) Epigenomics. 2019 May;11(6):619-638. (PMID: 31044623) Cancer Cell. 2011 Jan 18;19(1):17-30. (PMID: 21251613) Nucleic Acids Res. 2020 Sep 4;48(15):8360-8373. (PMID: 32619236) PLoS One. 2015 Mar 16;10(3):e0120200. (PMID: 25774516) J Mol Biol. 2018 Sep 14;430(18 Pt B):3081-3092. (PMID: 29981745) Metabolites. 2023 Mar 31;13(4):. (PMID: 37110165) Nucleic Acids Res. 2011 May;39(10):4151-65. (PMID: 21296759) Nat Biotechnol. 2011 Jan;29(1):24-6. (PMID: 21221095) Methods Enzymol. 2016;573:279-301. (PMID: 27372758) Cancer Cell. 2016 Aug 8;30(2):337-348. (PMID: 27424808) Curr Biol. 2015 Mar 2;25(5):546-55. (PMID: 25660547) J Inherit Metab Dis. 2012 Jul;35(4):571-87. (PMID: 22391998) Mol Cell. 2022 Feb 17;82(4):816-832.e12. (PMID: 35081363) Cell. 2007 Nov 16;131(4):633-6. (PMID: 18022353) Nature. 2012 Feb 15;483(7390):474-8. (PMID: 22343901) Nat Genet. 2018 Jan;50(1):62-72. (PMID: 29180699) Cell Rep. 2014 Mar 27;6(6):961-972. (PMID: 24613354) Trends Cancer. 2018 Feb;4(2):151-165. (PMID: 29458964) Nat Microbiol. 2016 Feb 01;1:15030. (PMID: 27572163) Nat Rev Cancer. 2020 Dec;20(12):710-726. (PMID: 33087883) |
المشرفين على المادة: | 2889-31-8 (alpha-hydroxyglutarate) EC 1.14.11.- (Histone Demethylases) 0 (Histones) 0 (Saccharomyces cerevisiae Proteins) 0 (RPH1 protein, S cerevisiae) |
تواريخ الأحداث: | Date Created: 20231127 Date Completed: 20231201 Latest Revision: 20240425 |
رمز التحديث: | 20240425 |
مُعرف محوري في PubMed: | PMC10681907 |
DOI: | 10.26508/lsa.202302333 |
PMID: | 38011998 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2575-1077 |
---|---|
DOI: | 10.26508/lsa.202302333 |