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

Nature Metabolism volume 3, pages 983–1000 (2021)Cite this article

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Abstract

Acetyl-CoA is a central node in carbon metabolism and plays critical roles in regulatory and biosynthetic processes. The acetyl-CoA synthetase Acs2, which catalyses acetyl-CoA production from acetate, is an integral subunit of the serine-responsive SAM-containing metabolic enzyme (SESAME) complex, but the precise function of Acs2 within the SESAME complex remains unclear. Here, using budding yeast, we show that Acs2 within the SESAME complex is required for the regulation of telomere silencing and cellular senescence. Mechanistically, the SESAME complex interacts with the histone acetyltransferase SAS protein complex to promote histone H4K16 acetylation (H4K16ac) enrichment and the occupancy of bromodomain-containing protein, Bdf1, at subtelomeric regions. This interaction maintains telomere silencing by antagonizing the spreading of Sir2 along the telomeres, which is enhanced by acetate. Consequently, dissociation of Sir2 from telomeres by acetate leads to compromised telomere silencing and accelerated chronological ageing. In human endothelial cells, ACSS2, the ortholog of yeast Acs2, also interacts with H4K16 acetyltransferase hMOF and are required for acetate to increase H4K16ac, reduce telomere silencing and induce cell senescence. Altogether, our results reveal a conserved mechanism to connect cell metabolism with telomere silencing and cellular senescence.

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Fig. 1: SESAME complex is required to maintain global H4K16ac and H4K16ac localization at subtelomeric regions.
Fig. 2: The SESAME complex interacts with the SAS complex to promote H4K16ac.
Fig. 3: The SESAME complex and Sas2 co-regulate gene transcription and telomere silencing.
Fig. 4: The SESAME complex and SAS complex are required for acetate to induce H4K16ac.
Fig. 5: Acetate enhances the binding of Bdf1 at subtelomeric regions.
Fig. 6: The SESAME and SAS complexes are required for acetate to antagonize Sir2-mediated telomere silencing.
Fig. 7: Acetate accelerates chronological ageing in yeast and induce senescence in HUVEC cells.
Fig. 8: Acetate accelerates cell senescence in HUVECs dependent on ACSS2 and hMOF.

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Data availability

The accession numbers for the Acs2 and H4K16ac ChIP–seq datasets reported in this paper are GSE146143 and PRJNA695438. The accession number for the Pyk1, Sam1 ChIP–seq dataset is GSE72972. The accession numbers for the H4K16ac ChIP–seq dataset are GSE52339 and GSE108217. The accession numbers for the raw RNA-seq dataset reported in this paper are PRJNA612967, PRJNA674443, PRJNA673282 and GSE147765. Uncropped blots and source data are provided with this paper. All other data are available from the authors upon reasonable request.

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Acknowledgements

We sincerely thank J. D. Boeke and J. Thorner for yeast strains and antibodies. We thank Igenebook Bioinformatics Institute (Wuhan, China) for technical support. This work was supported by funding from the National Natural Science Foundation of China (31970578 to S.L. and 31872812 to X.Y.), the Natural Science Foundation of Hubei Province (2019CFA077 to X.Y. and 2017CFA066 to S.L.), National Institutes of Health (1R35GM118068 to J.L.W.) and the Stowers Institute.

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Author notes

  1. These authors contributed equally: Wanping Chen, Xilan Yu.

Authors and Affiliations

  1. State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, China

    Wanping Chen, Xilan Yu, Yinsheng Wu, Jie Tang, Qi Yu, Xin Li, Jianguo Chen, Lixin Ma & Shanshan Li

  2. Human Aging Research Institute (HARI), School of Life Science, Nanchang University, Nanchang, China

    Xiaodong Lv & Zitong Zha

  3. The Central Laboratory, Wuhan No.1 Hospital, Wuhan, China

    Bicheng Hu

  4. Stowers Institute for Medical Research, Kansas City, MO, USA

    Jerry L. Workman

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Contributions

Conceptualization: S.L. and X.Y.; experiments with western blots, RNA-seq, ChIP–qPCR, ChIP–seq and Co-IP were performed by W.C., X.Y., J.T. and X.L.; experiments with cell culture were performed by Y.W., X.L. and Z.Z.; animal experiments were performed by Y.W. and B.H.; CL7 affinity purification was done by L.M.; ChIP–seq and RNA-seq data were analysed by Q.Y. and W.C.; statistical analysis was performed by X.Y., W.C. and J.C.; writing, review and editing: X.Y., S.L. and J. L.W.

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Correspondence to Shanshan Li.

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The authors declare no competing interests.

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Peer review information Nature Metabolism thanks Brian Kennedy and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: George Caputa.

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Extended data

Extended Data Fig. 1 The SESAME complex is required to maintain the normal levels of H4K16ac.

a Analysis of relative intracellular acetyl-CoA levels in WT, sam1∆ and ser33∆ mutants. The acetyl-CoA levels were normalized to intracellular protein concentrations. b and c Quantification of western blots data in Fig. 1d. d Western blot analysis of H4K16ac and Acs2 in WT, TEFpr-ACS2 and CYCpr-ACS2 mutants. e Western blot analysis of H4K16ac in WT, acs1Δ and ach1Δ mutants. f ChIP-qPCR analysis of H4K16ac in TEFpr-ACS2 and CYCpr-ACS2 at regions with different distance to TEL VI-R. g ChIP-qPCR analysis of H4K16ac in WT and acs2-ts mutant at subtelomere regions of chromosome V (TEL V XC and TEL V XR), and chromosome VII (TEL VII XC and TEL VII XR). h ChIP-qPCR analysis of Acs2 occupancy at subtelomere regions. KRE1 and YJR011C were used as negative control regions. The untagged BY4741 and IgG were used as negative controls. i ChIP analysis of the occupancy of Sam1 (Sam1-FLAG) at regions with different distance to telomere VI-R. The untagged BY4741 was used as a negative control. The IP signals were normalized to input signals. j Venn diagram showing the overlap of genes occupied by Acs2, Sam1 and Pyk1 as determined by ChIP-seq. Acs2-bound genes were co-occupied by Pyk1 and Sam1 with P = 1.26 × 10−372 and P = 6.15 × 10−356, respectively using hypergeometric test. k Heatmap shown the binding of Acs2 at regions located within 30 kb of all 32 telomeres as determined by ChIP-seq. For Extended Data Fig. 1a–i, data represent means ± SE; n = 3 biological independent experiments. Two-sided t-tests were used for statistical analysis.

Source data

Extended Data Fig. 2 The SESAME complex interacts with the SAS complex to promote H4K16ac.

a Analysis of the genetic interaction between ACS2 and SAS2, ACS2 and SAS3, ACS2 and SAS4, ACS2 and SAS5. WT, acs2-ts, sas2Δ, acs2-ts sas2Δ, sas3Δ, acs2-ts sas3Δ, sas4Δ, acs2-ts sas4Δ, sas5Δ, and acs2-ts sas5Δ mutants were grown on YPD plates at 26 °C and 37 °C for 2–4 days. b The SESAME complex interacts with Sas2. The endogenous Acs2-FLAG was immunoprecipitated from cell lysates of Sas2-13Myc and Sas2-13Myc/Acs2-FLAG strains with anti-FLAG antibody. The Sas2-13Myc strain was used as a negative control. The co-IPed proteins were detected with anti-Myc (Sas2-13Myc), anti-Sam1, anti-Pyk1 and anti-Shm2 antibodies. c Effect of Acs2 on Sas2 expression levels as determined by western blot analysis. d Acs2 is required to maintain the integrity of SAS complex as determined by in vivo Co-IP assay. The endogenously expressed Sas5-FLAG was immunoprecipitated with anti-FLAG antibody from Sas5-FLAG and Sas5-FLAG acs2-ts cells when grown at 37 °C for 2 hr. The co-IPed Sas2 were detected by anti-Sas2 antibody. e Inactivation of Acs2 has no effect on acetylation of SAS complex. Sas5 was immunoprecipitated with anti-Myc antibody. The acetylation of SAS complex was detected with anti-acetyl lysine antibody. Ada3-FLAG was immunoprecipitated with anti-FLAG antibody and detected with anti-acetyl lysine antibody as a positive control (lane 3). For Extended Data Fig. 2a,b,d,e, shown is the typical example of 3 biological independent replicates. For Fig. 2c, data represent mean ± SE; n = 3 biological independent experiments. Two-sided t-tests were used for statistical analysis.

Source data

Extended Data Fig. 3 The SESAME complex and SAS complex co-regulate gene expression and telomere silencing.

a KEGG analysis of genes co-occupied by Acs2, Sam1 and H4K16ac. See also Fig. 3a. b Boxplots showing the overall transcription changes in WT, acs2-ts, sam1Δ, sas2Δ, and H4K16R mutants. Centre lines denote medians; box limits denote 25th and 75th percentiles; whiskers denote maxima and minima. Two-sided t-tests were used for statistical analysis. c Left panel: Venn diagrams showing the overlap of genes co-regulated by Acs2 and Sam1. Genes with fold changes in acs2-ts (≥3-fold; ≤0.5-fold), sam1Δ (≥1.5-fold; ≤0.75-fold) and P < 0.05 were considered as differentially expressed. The significance for overlapped genes between acs2-ts and sam1Δ RNA-seq datasets was indicated by the P-value, which was calculated by hypergeometric test. Right panel: KEGG analysis of genes co-regulated by Acs2 and Sam1. d-g Histogram showing the fractions of genes down-regulated in sas2Δ (d), H4K16R (e), sam1Δ (f) and acs2-ts (g) when plotted as a function of their distance to the nearest telomeres. Genes were categorized at 10-kb intervals for up to 60 kb from telomeres. One-sided χ2 tests were used. *, χ2 > 3.841, P < 0.05; ***, χ2 > 10.828, P < 0.001. h RT–qPCR analysis of the transcription of telomere-proximal genes in TEFpr-ACS2 and CYCpr-ACS2. Data represent means ± SE; n = 3 biological independent experiments. Two-sided t-tests were used for statistical analysis.

Source data

Extended Data Fig. 4 Acetate induces the global levels of H4K16ac as well as H4K16ac at subtelomere regions.

a and b Western blot analysis of the effect of acetate on histone modifications in yeast cells. WT (BY4741) cells were treated with 0–50 mM KAc for 4 hr. c Effect of KCl on H4K16ac in WT (BY4741) cells as determined by western blots. KAc treatment was used as a positive control. d Effect of KAc and KCl treatment on the medium pH after yeast cells were grown for 24 hr. e-g Western blot analysis of the effect of NaCl and NaAc on histone modifications in WT (BY4741) cells. The asterisk (*) indicates non-specific bands. h and i ChIP-seq tracks of H4K16ac at indicated genes when cells were treated with KCl and KAc. j ChIP-qPCR analysis of the effect of acetate on H4K16ac at subtelomere regions (TEL VIR, TEL V XC, TEL V XR, TEL VII XC and TEL VII XR) and telomere-proximal genes (COS8, IRC7, YCR106W, PHO11, SOR1). k Effect of glucose on H4K16ac as determined by western blots. Log phased WT (BY4741) cells were treated with YP + 0.05% glucose, YP + 1% glucose and YP + 4% glucose for 2 hr. For Extended Data Fig. 4a–g,j,k, data represent means ± SE; n = 3 biological independent experiments. Two-sided t-tests were used for statistical analysis.

Source data

Extended Data Fig. 5 Acs2 and Sas2 are required for acetate to induce H4K16ac.

a Acetate has no significant effect on Acs2 protein levels as determined by western blots. WT (BY4741) cells were treated with 0–50 mM KAc for 4 hr. KCl was added to keep the concentration of K+ at 50 mM. b Effect of acetate on H4K16ac in WT TetO7 and TetO7-ACS2 mutants as determined by Western blots. WT TetO7 and TetO7-ACS2 mutant were treated with KAc and doxycycline (dox) for 0–5 hr. c Effect of acetate on H4K16ac in WT and sam1Δ mutant. d and e Effect of acetate on H4K16ac in acs1Δ (d) and ach1Δ (e) mutants. f Acetate has no significant effect on Sas2 occupancy at subtelomere regions as determined by ChIP-qPCR. g Acetate treatment had no effect on the interaction between Sas2 and Sas5 as determined by Co-IP assay. The Sas5-13Myc/Sas2-FLAG and Sas5-13Myc/Sas2-FLAG/acs2-ts cells were grown at 37 °C and treated with or without KAc for 4 hr. Sas5 (Sas5-13Myc) was immunoprecipitated with anti-Myc agarose from cell lysates. The co-IPed Sas2 was detected by anti-FLAG (Sas2-FLAG). For Extended Data Fig. 5a–f, data represent means ± SE; n = 3 biological independent experiments. Two-sided t-tests were used for statistical analysis. For Extended Data Fig. 5g, shown is the typical example of 2 biological independent replicates.

Source data

Extended Data Fig. 6 Acetate regulates telomere silencing in budding yeast.

a Histogram showing the fraction of genes down-regulated in bdf1Δ (≤0.75-fold, P < 0.05) when plotted as a function of their distance to the nearest telomere. Genes were categorized at 10-kb intervals for up to 60 kb from telomeres. One-sided χ2 tests were used. *, χ2 > 3.841, P < 0.05; ***, χ2 > 10.828, P < 0.001. b Effect of Acs2 on Bdf1 expression as determined by western blots. c Effect of Bdf1 on the global levels of H4K16ac as determined by western blots. d ChIP analysis of H4K16ac at TEL V and TEL VII regions in WT and bdf1Δ mutant. e Effect of acetate on Bdf1 occupancy at subtelomere regions (TEL V XC, TEL V XR, TEL VII XC and TEL VII XR) as determined by ChIP-qPCR analysis. f ChIP-qPCR analysis of Sir2 occupancy at regions with different distance to TEL VI-R in TEFpr-ACS2 and CYCpr-ACS2. g Effect of Acs2 on Sir2 protein levels as determined by western blots. WT and acs2-ts mutant were grown at 37 °C for 2 hr. h ChIP-qPCR analysis of the effect of acetate on Sir2 binding at telomere-proximal genes in acs2-ts mutant. KCl was added as a control. i and j RT–qPCR analysis of the effect of KAc and sodium acetate (NaAc) on the transcription of telomere-proximal genes. KCl and NaCl were used as controls. k and l qRT-PCR analysis of the effect of acetate on the transcription of telomere-proximal genes in sam1Δ (k) and acs2-ts (l) mutants. m qRT-PCR analysis of the transcription of telomere-proximal genes in WT cells treated with YP + 2% glucose, 0.5% glucose, 0.05% glucose, 2% glycerol, 2% ethanol. For Extended Data Fig. 6b–m, data represent means ± SE; n = 3 biological independent experiments, two-sided t-tests were used for statistical analysis.

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Extended Data Fig. 7 Acetate accelerates chronological aging in budding yeast.

a Boxplots showing the overall transcription changes by KAc treatment. Centre lines denote medians; box limits denote 25th and 75th percentiles; whiskers denote maxima and minima. Two-sided t-tests were used for statistical analysis. b Histogram showing the number of genes up-regulated by KAc treatment but down-regulated in sas2Δ (KAc up/sas2Δ down), H4K16R (KAc up/H4K16R down), bdf1Δ (KAc up/bdf1Δ down) when plotted as a function of their distance to the nearest telomere. Genes were categorized at 10-kb intervals for up to 60 kb from telomeres. One-sided χ2 tests were used. ***, χ2 > 10.828, P < 0.001. c-d Quantification of western blots data in Fig. 7e,f. e Analysis of the chronological life span of TEFpr-ACS2, CYCpr-ACS2, TEFpr-ACS2 sir2Δ, and CYCpr-ACS2 sir2Δ. f Analysis of the effect of acetate on the chronological life span of Sir2 overexpression cells (Sir2 OE, BY4741 genetic background). Cells (BY4741) transformed with the empty vector (EV) were used as a control. The survival percentage of cells on day 11 and day 25 was presented on the left panel. g Effect of acetate on autophagy in cells expressing the endogenous ATG8 promoter-driven GFP-ATG8. The autophagy activity was determined by a GFP (green fluorescent protein) liberation assay, which detects free GFP that is cleaved upon the delivery of endogenous promoter-driven Atg8 with an N-terminal GFP tag (GFP-Atg8) to the vacuole and subsequent proteolysis of Atg8. For Extended Data Fig. 7c–g, data represent means ± SE; n = 3 biological independent experiments, two-sided t-tests were used for statistical analysis.

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Extended Data Fig. 8 Acetate accelerates cell senescence in HUVEC.

a Effect of acetate on HUVEC cell growth. b Effect of acetate on HUVEC cell cycle profiling. c-e Quantification of western blots data in Fig. 8a,b,e. f Effect of glucose (Gluc) starvation on H4K16ac in control (siControl) and ACSS2 knockdown (siACSS2) HUVEC cells. Cells were depleted of glucose for 6 hr. g Effect of glucose (Gluc) starvation on senescence of control (siControl) and ACSS2 knockdown (siACSS2) HUVEC cells as determined by SA-β-gal staining. Scale bar, 25 μm. Right panel: Quantification of the percentage of SA-β-gal positive cells. h Effect of glucose starvation on transcription of IL1A, IL1B, p16 and p21 in control (siControl) and ACSS2 knockdown (siACSS2) HUVEC cells. For Extended Data Fig. 8a–h, the quantitative data represent the mean ± SE; n = 3 biological independent experiments; two-sided t-tests were used for statistical analysis.

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Extended Data Fig. 9 Acetate accelerates cell senescence dependent on ACSS2 and hMOF.

a Effect of acetate on H4K16ac in control (siControl) and MATIIα knockdown (siMATIIα) HUVEC cells. b and c Effect of acetate on senescence of control (siControl) and MATIIα knockdown (siMATIIα) cells as determined by SA-β-gal staining (b) and SAHF detection (DAPI staining) (c). d Quantification of western blots data in Fig. 8g. e Effect of acetate on H4K16ac in control and SIRT1 overexpression (SIRT1 OE) HUVEC cells. f Effect of acetate on senescence of control and SIRT1 overexpression (SIRT1 OE) HUVEC cells as determined by SA-β-gal staining. g KEGG analysis of 2533 genes differentially regulated by KAc. h Top panel: Venn diagrams showing the overlap between genes down-regulated by siACSS2 but up-regulated by KAc treatment. Bottom panel: Venn diagrams showing the overlap between genes up-regulated by siACSS2 but down-regulated by KAc treatment. i Heatmap showing genes differentially regulated by ACSS2 and acetate. j Effect of acetate and ACSS2 on telomere length in young (P10) and senescent (P22) HUVEC cells. For Extended Data Fig. 9a–f,j, the quantitative data represent the mean ± SE; n = 3 biological independent experiments; two-sided t-tests were used for statistical analysis.

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Extended Data Fig. 10 A working model for how acetate regulates telomere silencing and aging in budding yeast.

a Under normal conditions, Acs2 within the SESAME complex synthesizes acetyl-CoA from glucose-derived acetate. SESAME specifically maintains normal levels of H4K16ac at subtelomere regions via its interaction with SAS complex. By promoting the binding of Bdf1, H4K16ac functions as the telomeric heterochromatin-euchromatin boundary to prevent the spreading of SIR complex. b When cells were treated with acetate, the interaction between the SESAME complex and the SAS complex is enhanced, which then increases Sas2-catalyzed H4K16ac and Bdf1 binding across the subtelomere regions. As a consequence, Sir2 is dissociated from the telomeres, leading to compromised telomere silencing and accelerated aging in yeast.

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Chen, W., Yu, X., Wu, Y. et al. The SESAME complex regulates cell senescence through the generation of acetyl-CoA. Nat Metab 3, 983–1000 (2021). https://doi.org/10.1038/s42255-021-00412-9

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