Epigenetic regulation of intracellular branched-chain amino acid homeostasis maintains a normal lifespan
Summary: Cells experience a progressive decline in function and lifespan, accompanied by epigenetic changes. Here, we show that intracellular BCAA (icBCAA) homeostasis is regulated by histone H3K4 and H3K121 in budding yeast. Using a comprehensive H3/H4 mutant library, we identified residues essenti...
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| Language: | English |
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Elsevier
2025-07-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225011071 |
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| author | Sejung Park Yan Liu Suji Lim Hong-Yeoul Ryu Seong Hoon Ahn |
| author_facet | Sejung Park Yan Liu Suji Lim Hong-Yeoul Ryu Seong Hoon Ahn |
| author_sort | Sejung Park |
| collection | DOAJ |
| description | Summary: Cells experience a progressive decline in function and lifespan, accompanied by epigenetic changes. Here, we show that intracellular BCAA (icBCAA) homeostasis is regulated by histone H3K4 and H3K121 in budding yeast. Using a comprehensive H3/H4 mutant library, we identified residues essential for lifespan maintenance linked to BCAA metabolism. Among these, H3K4A/R and H3K121A mutations led to significant transcriptional changes in genes involved in BCAA biosynthesis and catabolism, accompanied by abnormally elevated icBCAA levels. Consistent with the upregulation of BAT1, ILV6, and ADH1 genes in the H3K121A mutant, chromatin immunoprecipitation revealed increased H3K4me3 at their promoters. The genetic perturbation of BAT1 and BAT2 restored icBCAA balance and partially rescued lifespan defects in H3K4 or H3K121 mutants. Additionally, H3K4 and H3K121 mutations affected lifespan regulation through TORC1 signaling. Our findings suggest that the epigenetic control of BCAA metabolism, specifically through the modification of histone residues, contributes to maintaining metabolic homeostasis and replicative lifespan. |
| format | Article |
| id | doaj-art-b201013a17fe42998d267faf0f032fb0 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-b201013a17fe42998d267faf0f032fb02025-08-20T03:30:30ZengElsevieriScience2589-00422025-07-0128711284610.1016/j.isci.2025.112846Epigenetic regulation of intracellular branched-chain amino acid homeostasis maintains a normal lifespanSejung Park0Yan Liu1Suji Lim2Hong-Yeoul Ryu3Seong Hoon Ahn4Department of Medicinal and Life Science, College of Science and Convergence Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of KoreaDepartment of Medicinal and Life Science, College of Science and Convergence Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of KoreaDepartment of Medicinal and Life Science, College of Science and Convergence Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of KoreaBK21 Plus KNU Creative BioResearch Group, School of Life Sciences, College of National Sciences, Kyungpook National University, Daegu 41566, Republic of KoreaDepartment of Medicinal and Life Science, College of Science and Convergence Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of Korea; Corresponding authorSummary: Cells experience a progressive decline in function and lifespan, accompanied by epigenetic changes. Here, we show that intracellular BCAA (icBCAA) homeostasis is regulated by histone H3K4 and H3K121 in budding yeast. Using a comprehensive H3/H4 mutant library, we identified residues essential for lifespan maintenance linked to BCAA metabolism. Among these, H3K4A/R and H3K121A mutations led to significant transcriptional changes in genes involved in BCAA biosynthesis and catabolism, accompanied by abnormally elevated icBCAA levels. Consistent with the upregulation of BAT1, ILV6, and ADH1 genes in the H3K121A mutant, chromatin immunoprecipitation revealed increased H3K4me3 at their promoters. The genetic perturbation of BAT1 and BAT2 restored icBCAA balance and partially rescued lifespan defects in H3K4 or H3K121 mutants. Additionally, H3K4 and H3K121 mutations affected lifespan regulation through TORC1 signaling. Our findings suggest that the epigenetic control of BCAA metabolism, specifically through the modification of histone residues, contributes to maintaining metabolic homeostasis and replicative lifespan.http://www.sciencedirect.com/science/article/pii/S2589004225011071Properties of biomoleculesMolecular geneticsEpigeneticsMicrobial metabolism |
| spellingShingle | Sejung Park Yan Liu Suji Lim Hong-Yeoul Ryu Seong Hoon Ahn Epigenetic regulation of intracellular branched-chain amino acid homeostasis maintains a normal lifespan iScience Properties of biomolecules Molecular genetics Epigenetics Microbial metabolism |
| title | Epigenetic regulation of intracellular branched-chain amino acid homeostasis maintains a normal lifespan |
| title_full | Epigenetic regulation of intracellular branched-chain amino acid homeostasis maintains a normal lifespan |
| title_fullStr | Epigenetic regulation of intracellular branched-chain amino acid homeostasis maintains a normal lifespan |
| title_full_unstemmed | Epigenetic regulation of intracellular branched-chain amino acid homeostasis maintains a normal lifespan |
| title_short | Epigenetic regulation of intracellular branched-chain amino acid homeostasis maintains a normal lifespan |
| title_sort | epigenetic regulation of intracellular branched chain amino acid homeostasis maintains a normal lifespan |
| topic | Properties of biomolecules Molecular genetics Epigenetics Microbial metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225011071 |
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