The SESAME complex regulates cell senescence through the generation of acetyl-CoA

Chen, Wanping; Yu, Xilan; Wu, Yinsheng; Tang, Jie; Yu, Qingxu; Liu, Xiaodong; Zha, Zitong; Hu, Bingbing; Li, Xin; Chen, Jianguo; Ma, Lixin; Workman, Jerry L.; Li, Shanshan

doi:10.1038/s42255-021-00412-9

Cited by 27 publications

(20 citation statements)

References 51 publications

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“…2b ). The reduced H4K16ac could be caused by reduced production of acetyl-CoA within the context of SESAME complex and impaired function of H4K16 acetyltransferase SAS complex 31 . We thus examined the genome-wide occupancy of H4K16ac in WT and pyk1-ts mutant by ChIP-seq.…”

Section: Resultsmentioning

confidence: 99%

“…Antibodies against anti-H3 (1:5000; ab1791), anti-H4 (1:5000; ab10158) and H3pT11 (1:5000; ab5168) were purchased from Abcam; antibodies against H3K79me1 (1: 1000; A2367), H3K79me2 (1: 5000; A2368), H3K79me3 (1:5000; A2369), anti-His (1:5000; AE0039) and anti-FLAG (1:5000; AE024) were purchased from Abclonal; antibody against Sir2 (1:500; sc-6667) was purchased from Santa Cruz Biotechnology; antibodies against GAPDH (1:10,000; 10494-1-AP), GFP (1:5000; 66002-1-1 g), Myc (1:5000; 60003-2-1 g), goat polyclonal anti-mouse IgG (1:5000; SA00001-1) and goat polyclonal anti-rabbit IgG (1:5000; SA00001-2) were obtained from Proteintech; antibody against FLAG M2 (1:3000; F1804-1MG) was obtained from Sigma-Aldrich; antibody against H4K16ac (1:2000; 07-329) was obtained from EMD Millipore; antibody against CBP (1:2000; Abs130593) was purchased from Absin Bioscience Inc. The custom-made antibodies against Acs2, Pyk1, Sam1 and Shm2 were produced by Covance Inc. and their specificity was verified by immunoblots of cell lysates of the corresponding histone point mutants, gene deletion or knockdown mutants 31 .…”

Section: Methodsmentioning

confidence: 99%

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SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing

Wang

et al. 2022

Nat Commun

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The glycolytic enzyme, pyruvate kinase Pyk1 maintains telomere heterochromatin by phosphorylating histone H3T11 (H3pT11), which promotes SIR (silent information regulator) complex binding at telomeres and prevents autophagy-mediated Sir2 degradation. However, the exact mechanism of action for H3pT11 is poorly understood. Here, we report that H3pT11 directly inhibits Dot1-catalyzed H3K79 tri-methylation (H3K79me3) and uncover how this histone crosstalk regulates autophagy and telomere silencing. Mechanistically, Pyk1-catalyzed H3pT11 directly reduces the binding of Dot1 to chromatin and inhibits Dot1-catalyzed H3K79me3, which leads to transcriptional repression of autophagy genes and reduced autophagy. Despite the antagonism between H3pT11 and H3K79me3, they work together to promote the binding of SIR complex at telomeres to maintain telomere silencing. Furthermore, we identify Reb1 as a telomere-associated factor that recruits Pyk1-containing SESAME (Serine-responsive SAM-containing Metabolic Enzyme) complex to telomere regions to phosphorylate H3T11 and prevent the invasion of H3K79me3 from euchromatin into heterochromatin to maintain telomere silencing. Together, these results uncover a histone crosstalk and provide insights into dynamic regulation of silent heterochromatin and autophagy in response to cell metabolism.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing

Wang

et al. 2022

Nat Commun

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“…The yeast chronological life span was performed as described previously ( Mei et al, 2019 ; Chen et al, 2021 ). Briefly, a total of 5 ml of seed cultures from individual colonies were grown overnight at 30°C in YPD medium.…”

Section: Methodsmentioning

confidence: 99%

Regulation of telomere silencing by the core histones–autophagy–Sir2 axis

Mei

et al. 2022

Life Sci. Alliance

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Telomeres contain compacted heterochromatin, and genes adjacent to telomeres are subjected to transcription silencing. Maintaining telomere structure integrity and transcription silencing is important to prevent the occurrence of premature aging and aging-related diseases. How telomere silencing is regulated during aging is not well understood. Here, we find that the four core histones are reduced during yeast chronological aging, leading to compromised telomere silencing. Mechanistically, histone loss promotes the nuclear export of Sir2 and its degradation by autophagy. Meanwhile, reducing core histones enhances the autophagy pathway, which further accelerates autophagy-mediated Sir2 degradation. By screening the histone mutant library, we identify eight histone mutants and one histone modification (histone methyltransferase Set1-catalyzed H3K4 trimethylation) that regulate telomere silencing by modulating the core histones–autophagy–Sir2 axis. Overall, our findings reveal core histones and autophagy as causes of aging-coupled loss of telomere silencing and shed light on dynamic regulation of telomere structure during aging.

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“…This complex balances glucose availability with glycolytic flux through the combined modulation of SAM and ATP availability for H3K4 methylation and H3T11 phosphorylation on histones of the promoter of the yeast PKM2 homolog Pyk1 ( Li et al, 2015 ). In a separate study, the acetyl-CoA generating subunit of SESAME, ACS2, was found to promote histone H4K16 acetylation (H4K16ac) enrichment at subtelomeric regions through direct complexation with the histone acetyltransferase SAS protein complex ( Chen et al, 2021 ). Complexation of metabolic enzymes with transcription factors and epigenetic modifiers would thus integrate metabolism into the complex epigenetic machinery that shapes chromatin.…”

Section: Nuclear Metabolic and Epigenetic Enzymes Complexes On Chromatinmentioning

confidence: 99%

Metabolic Fuel for Epigenetic: Nuclear Production Meets Local Consumption

Boon

2021

Front. Genet.

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Epigenetic modifications are responsible for finetuning gene expression profiles to the needs of cells, tissues, and organisms. To rapidly respond to environmental changes, the activity of chromatin modifiers critically depends on the concentration of a handful of metabolites that act as substrates and co-factors. In this way, these enzymes act as metabolic sensors that directly link gene expression to metabolic states. Although metabolites can easily diffuse through the nuclear pore, molecular mechanisms must be in place to regulate epigenetic marker deposition in specific nuclear subdomains or even on single loci. In this review, I explore the possible subcellular sites of metabolite production that influence the epigenome. From the relationship between cytoplasmic metabolism and nuclear metabolite deposition, I converse to the description of a compartmentalized nuclear metabolism. Last, I elaborate on the possibility of metabolic enzymes to operate in phase-separated nuclear microdomains formed by multienzyme and chromatin-bound protein complexes.

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The SESAME complex regulates cell senescence through the generation of acetyl-CoA

Cited by 27 publications

References 51 publications

SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing

SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing

Regulation of telomere silencing by the core histones–autophagy–Sir2 axis

Metabolic Fuel for Epigenetic: Nuclear Production Meets Local Consumption

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