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Mono-unsaturated fatty acids link H3K4me3 modifiers to C. elegans lifespan

Abstract

Chromatin and metabolic states both influence lifespan, but how they interact in lifespan regulation is largely unknown. The COMPASS chromatin complex, which trimethylates lysine 4 on histone H3 (H3K4me3), regulates lifespan in Caenorhabditis elegans. However, the mechanism by which H3K4me3 modifiers affect longevity, and whether this mechanism involves metabolic changes, remain unclear. Here we show that a deficiency in H3K4me3 methyltransferase, which extends lifespan, promotes fat accumulation in worms with a specific enrichment of mono-unsaturated fatty acids (MUFAs). This fat metabolism switch in H3K4me3 methyltransferase-deficient worms is mediated at least in part by the downregulation of germline targets, including S6 kinase, and by the activation of an intestinal transcriptional network that upregulates delta-9 fatty acid desaturases. Notably, the accumulation of MUFAs is necessary for the lifespan extension of H3K4me3 methyltransferase-deficient worms, and dietary MUFAs are sufficient to extend lifespan. Given the conservation of lipid metabolism, dietary or endogenous MUFAs could extend lifespan and healthspan in other species, including mammals.

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Figure 1: H3K4me3 methyltransferase deficiency in the germline leads to fat accumulation in the intestine.
Figure 2: H3K4me3 methyltransferase deficiency results in elevated MUFAs and upregulation of delta-9 desaturases.
Figure 3: H3K4me3 methyltransferase germline targets influence fat metabolism.
Figure 4: Accumulation of MUFAs is critical for the longevity of H3K4me3 methyltransferase-deficient worms.
Figure 5: Dietary supplementation with MUFAs is sufficient to extend lifespan.

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Acknowledgements

We thank A. Jose, A. Rechtsteiner, S. Strome and R. Waterston for sharing expression data and strains pre-publication; A. Fire, M. Hansen, S. Kim, F. Palladino, D. Pattabiraman, Y. Zhang and the Caenorhabditis Genetics Center for plasmids and strains; M. Hansen, E. O’Rourke, L. Booth, C-K. Hu, D. Leeman, J. Lim and S. Mahmoudi for reading the manuscript; A. Fire, O. Gozani, S. Kim and Brunet laboratory members for discussions; A. Chien for GC–MS consulting; and J. Coller at the Stanford Functional Genomics Facility. Supported by NIH DP1AG044848 (A.B.), NIH R01AG054201 (A.B. and W.B.M.), NIH R01AG044346 (W.B.M.), a Stanford Mass Spectrometry grant (S.H. and A.B.), NSF Graduate Research Fellowship, Stanford Graduate Fellowship and NIH T32AG047126 (S.H.), and NIH T32AG047126 and NIH F32AG051337 (E.A.S.).

Author information

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Authors

Contributions

S.H. conceived the study under the guidance of A.B. S.H. performed all the experiments except those specified below. E.A.S. planned and performed Nile Red and FAT-5/FAT-7 reporter imaging, time-course RT–qPCR and one oleic acid supplementation lifespan experiment. C.G.S.-G. planned and performed SBP-1 localization experiments and generated set-2 transgenic lines under the guidance of W.B.M. K.H. analysed the RNA-seq data. S.H. wrote the paper with the help of A.B. and E.A.S. C.G.S.-G., K.H. and W.B.M. provided feedback.

Corresponding author

Correspondence to Anne Brunet.

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The authors declare no competing financial interests.

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Reviewer Information Nature thanks H. Aguilaniu, M. Kaeberlein and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Figure 1 Deficiency in H3K4me3 modifiers leads to fat accumulation in the intestine without altering fertility.

a, ORO quantification. Mean ± s.d., n ≥ 17 worms per condition. b, ORO images. Scale bars, 100 μm. c, ORO quantification. Mean ± s.d., n ≥ 9 dissected intestines per condition. d, e, Nile Red staining and quantification. Mean ± s.d., n ≥ 7 dissected intestines (d) or n ≥ 11 worms (e) per condition. Scale bars, 100 μm. f, Autofluorescence and quantification. Mean ± s.d., n ≥ 17 worms per condition. Scale bars, 100 μm. g, Fertility quantification of live brood size (i), fertilized eggs (ii), and unfertilized oocytes (iii) laid per worm. Mean ± s.d., n ≥ 25 worms per condition. h, RT–qPCR. Mean ± s.e.m. of two independent experiments, each with two or three biological replicates. i, RT–qPCR. Mean ± s.e.m. from two independent experiments, each with two or three biological replicates. j, ORO quantification. Mean ± s.d., n ≥ 26 worms per condition. k, ORO quantification. Mean ± s.d., n ≥ 29 worms per condition. l, RT–qPCR. Mean ± s.e.m. of three biological replicates. m, Differential interference contrast (DIC) (Nomarski) and GFP fluorescence images. n, ORO quantification. Mean ± s.d., n ≥ 26 worms per condition. af, k (rescue line number 1), n, Representative of two experiments. P values: a, cg, two-tailed Mann–Whitney; h, i, two-tailed Mann–Whitney with Benjamini–Hochberg correction; j, k, n, Kruskal–Wallis with Dunn’s correction; l, two-tailed t-test with Benjamini–Hochberg correction. *P < 0.05, **P < 0.01.

Extended Data Figure 2 The delta-9 desaturases FAT-5 and FAT-7 support MUFA accumulation in H3K4me3 methyltransferase-deficient worms.

a, GC–MS quantification of MUFAs. Mean ± s.e.m. of two independent experiments, each with three biological replicates. b, c, RT–qPCR. Mean ± s.e.m. of two independent experiments, each with three biological replicates. d, GC–MS quantification of MUFAs. Mean ± s.e.m. of two independent experiments, each with two or three biological replicates. e, RT–qPCR. Mean ± s.e.m. of two independent experiments, each with three biological replicates. P values: ae, two-tailed Mann–Whitney with Benjamini–Hochberg correction. *P < 0.05, **P < 0.01.

Extended Data Figure 3 RNA-seq on micro-dissected germlines and intestines and functional validation of ASH-2 targets.

a, RNA-seq tissue sample collection pipeline. b, Principal component analysis (PCA) with both intestinal and germline samples (left), only intestinal samples (middle) or only germline samples (right). c, RT–qPCR. Mean ± s.e.m. of two independent experiments, each with two or three biological replicates. d g, ORO quantification. Mean ± s.d., n ≥ 15 worms per condition. h, RT–qPCR. Mean ± s.e.m. of two independent experiments, each with three biological replicates. i, j, ORO quantification. Mean ± s.d., n ≥ 21 (i) and n ≥ 27 (j) worms per condition. k, RT–qPCR. Mean ± s.e.m. of two independent experiments, each with three biological replicates. l, GC–MS. Mean ± s.e.m. of two independent experiments, each with three biological replicates. m, ORO quantification. Mean ± s.d., n ≥ 19 worms per condition. n, RT–qPCR. Mean ± s.e.m. of two independent experiments, each with three biological replicates. o, Lifespan extension by ash-2 RNAi is reduced in rsks-1 mutants (13.12%) compared to wild-type worms (29.20%) (P < 0.0001, two-way ANOVA). p, let-363 RNAi and daf-15 RNAi extend lifespan in wild-type worms (P < 0.0001, log-rank), but not in set-2 mutants. d (except rrf-1 data), i, j, Representative of two experiments. P values: c, k, l, n, two-tailed Mann–Whitney with Benjamini–Hochberg correction; h, two-tailed Mann-Whitney; dg, i, j, m, Kruskal–Wallis with Dunn’s correction. *P < 0.05, **P < 0.01.

Extended Data Figure 4 Role of SBP-1, MDT-15, NHR-49 and NHR-80 in the fat accumulation and longevity of H3K4me3 methyltransferase-deficient worms.

ad, Images and quantification of SBP-1 nuclear accumulation. Mean ± s.d. of two independent experiments, each with 4–6 nuclei per worm of ≥ 8 worms per condition. e, RT–qPCR. Mean ± s.e.m. of two independent experiments, each with three biological replicates. f, GC–MS quantification of MUFAs. Mean ± s.e.m. of two independent experiments, each with two or three biological replicates. g, ORO quantification. Mean ± s.d., n ≥ 21 worms per condition. h, ash-2 RNAi extends lifespan in wild-type worms (P < 0.0001, log-rank), but not in mdt-15 RNAi worms. i, ORO quantification, Mean ± s.d., n ≥ 24 worms per condition. j, ash-2 RNAi extends lifespan in both wild-type worms and nhr-49 mutants (P < 0.0001, log-rank). k, ORO quantification. Mean ± s.d., n ≥ 27 worms per condition. l, ash-2 RNAi extends lifespan in both wild-type worms and nhr-80 mutants (P < 0.0001, log-rank). ik, Representative of two experiments. P values: a, two-tailed Mann–Whitney; bd, g, i, k, Kruskal–Wallis with Dunn’s correction; e, f, two-tailed Mann–Whitney with Benjamini–Hochberg correction. *P < 0.05.

Extended Data Figure 5 Delta-9 desaturases FAT-6 and FAT-7 and MUFA oleic acid mediate the longevity of H3K4me3 methyltransferase-deficient worms.

a, ORO quantification. Mean ± s.d., n ≥ 29 worms per condition. b, ash-2 RNAi leads to lifespan extension in control (P < 0.0001, log-rank), but not in fat-6 and fat-7 double mutants. c, ash-2 RNAi extends lifespan in both wild-type worms and fat-7 single mutants (P < 0.0001, log-rank). d, ash-2 RNAi extends lifespan in fat-6 single mutants (P = 0.0162, log-rank), but lifespan extension by ash-2 RNAi is reduced in fat-6 mutants (9.26%) compared to wild-type worms (20.46%) (P = 0.0072, two-way ANOVA). e, ash-2 RNAi extends lifespan in fat-5 and fat-7 double mutants (P < 0.0001, log-rank). f, ash-2 RNAi extends lifespan in fat-5 and fat-6 double mutants (P = 0.0002, log-rank), but lifespan extension by ash-2 RNAi is reduced in fat-5 and fat-6 double mutants (14.03%) compared to wild-type worms (20.46%) (P = 0.0358, two-way ANOVA). g, h, GC–MS quantification of oleic acid. Mean ± s.e.m. of three biological replicates. i, ORO quantification. Mean ± s.d., n ≥ 13 worms per condition. Boxed conditions are identical to Fig. 4g. j, Oleic acid supplementation extends lifespan (P < 0.0001, log-rank), which is not further extended by ash-2 RNAi. Oleic acid supplementation extends lifespan in ash-2 and fat-7 double RNAi worms (P < 0.0001, log-rank). Boxed conditions are identical to Fig. 4h. k, ORO quantification. Mean ± s.d., n ≥ 21 worms per condition. l, GC–MS quantification of MUFAs. Mean ± s.e.m. of two independent experiments, each with two or three biological replicates. m, RT–qPCR. Mean ± s.e.m. of two independent experiments, each with three biological replicates. n, ORO quantification. Mean ± s.d., n ≥ 25 worms per condition. o, ash-2 RNAi extends lifespan in control (P < 0.0001, log-rank) but not fat-2 RNAi worms. c, i, j, n, o, Representative of two experiments. P values: a, gi, k, n, Kruskal–Wallis with Dunn’s correction; l, m, two-tailed Mann–Whitney with Benjamini–Hochberg correction. *P < 0.05, **P < 0.01.

Extended Data Figure 6 Dietary supplementation with MUFAs, but not PUFAs, extends lifespan in wild-type worms.

a, GC–MS. Mean ± s.e.m. of two independent experiments, each with two or three biological replicates. b, Cis-vaccenic acid supplementation extends lifespan in wild-type worms (P < 0.0001, log-rank). Inset: ORO quantification. Mean ± s.d., n ≥ 20 worms per condition. c, GC–MS. Mean ± s.e.m. of two independent experiments, each with three biological replicates. d, Linoleic acid supplementation does not extend lifespan in wild-type worms. Inset: ORO quantification. Mean ± s.d., n ≥ 23 worms per condition. e, GC–MS. Mean ± s.e.m. of two independent experiments, each with three biological replicates. f, Alpha-linolenic acid supplementation does not increase the lifespan of wild-type worms. Inset: ORO quantification. Mean ± s.d., n ≥ 23 worms per condition. g, RT–qPCR. Mean ± s.e.m. of three biological replicates. h, ORO quantification. Mean ± s.d., n ≥ 54 worms per condition. i, Overexpression of FAT-7 extends lifespan (P < 0.0001, log-rank), but this lifespan is not extended further by dietary oleic acid. Boxed regions are identical to Fig. 5g. j, Proposed model by which ash-2 deficiency in the germline could lead to the fat metabolic switch in the intestine. b, d, f, Representative of two experiments. P values: a, c, e, two-tailed Mann–Whitney with Benjamini–Hochberg correction; b inset, d inset, f inset, two-tailed Mann–Whitney; g, Kruskal–Wallis test with Dunn’s correction (non-significant, probably owing to small sample size). One-way ANOVA with Bonferroni’s correction. h, Kruskal–Wallis with Dunn’s correction; *P < 0.05, **P < 0.01, ***P < 0.001.

Extended Data Table 1 List of ASH-2 candidate targets

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Han, S., Schroeder, E., Silva-García, C. et al. Mono-unsaturated fatty acids link H3K4me3 modifiers to C. elegans lifespan. Nature 544, 185–190 (2017). https://doi.org/10.1038/nature21686

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