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Early life changes in histone landscape protect against age-associated amyloid toxicities through HSF-1-dependent regulation of lipid metabolism

Nature Aging volume 4, pages 48–61 (2024)Cite this article

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Abstract

Transient events during development can exert long-lasting effects on organismal lifespan. Here we demonstrate that exposure of Caenorhabditis elegans to reactive oxygen species during development protects against amyloid-induced proteotoxicity later in life. We show that this protection is initiated by the inactivation of the redox-sensitive H3K4me3-depositing COMPASS complex and conferred by a substantial increase in the heat-shock-independent activity of heat shock factor 1 (HSF-1), a longevity factor known to act predominantly during C. elegans development. We show that depletion of HSF-1 leads to marked rearrangements of the organismal lipid landscape and a significant decrease in mitochondrial β-oxidation and that both lipid and metabolic changes contribute to the protective effects of HSF-1 against amyloid toxicity. Together, these findings link developmental changes in the histone landscape, HSF-1 activity and lipid metabolism to protection against age-associated amyloid toxicities later in life.

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Fig. 1: Disruption of H3K4me3 modifiers protects C. elegans against amyloid toxicity.
Fig. 2: Protective effect of H3K4me3 depletion is due to HSF-1-mediated FAT-7 upregulation.
Fig. 3: Oleic acid protects against proteotoxicity in an HSF-1-dependent manner.
Fig. 4: Disruption of HSF-1 remodels the lipid landscape.
Fig. 5: Differential regulation of lipid metabolism by HSF-1 governs resistance to proteotoxicity in the absence of ash-2.

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Data availability

RNA-seq data are deposited in the Gene Expression Omnibus repository, available at: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE227652.

All other data that support the findings of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper.

Code availability

No original code was generated in this study.

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Acknowledgements

We thank the Csankovszki laboratory for providing us with RNAi bacteria and the members of the Jakob and Bardwell laboratories for many helpful discussions. This work was supported by National Institutes of Health (NIH) grant R35 GM122506 and National Institute of Aging grant R21 AG078540 to U.J., a Bright Focus ADR Fellowship (A2019250F) to B.J.O. and a University of Michigan T32-AG000114 Career Training in the Biology of Aging Training Grant to B.J.O. and D.B. In addition, the work was supported by University of Maryland School of Pharmacy Faculty Start-up funds, the University of Maryland School of Pharmacy Mass Spectrometry Center (SOP1841-IQB2014) and NIH R21NS117867 award to J.W.J.

Author information

Author notes

  1. Daphne Bazopoulou

    Present address: Department of Biology, University of Crete, Heraklion, Greece

  2. These authors contributed equally: Janakraj Bhattrai, Sarah L. Zalubas.

Authors and Affiliations

  1. Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, USA

    Bryndon J. Oleson, Janakraj Bhattrai, Sarah L. Zalubas, Tessa R. Kravchenko, Emily L. Jiang, Christine C. Lu, Ciara R. Madden, Julia G. Coffman, Daphne Bazopoulou & Ursula Jakob

  2. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA

    Yuanyuan Ji & Jace W. Jones

  3. Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA

    Ursula Jakob

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Contributions

B.J.O.: conceptualization, investigation, formal analysis, methodology, supervision, writing—original draft and writing—review and editing. J.B.: conceptualization and investigation. S.L.Z.: investigation and methodology. T.R.K.: investigation. Y.J.: investigation and formal analysis. E.L.J.: investigation. C.C.L.: investigation. C.R.M.: investigation. J.G.C.: investigation. D.B.: conceptualization. J.W.J.: methodology, formal analysis, resources, project administration, supervision and funding acquisition. U.J.: conceptualization, project administration, supervision, funding acquisition, writing—original draft and writing—review and editing.

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Correspondence to Ursula Jakob.

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Extended data

Extended Data Fig. 1 Amyloid levels and polyQ foci formation in H3K4me3 modifier-deficient C. elegans (related to Fig. 1).

(a, b) Levels of Aβ1-42 in CL4176 worms maintained on L4440, ash-2 or set-2 RNAi were assessed by western blot (a) and quantified by densitometry (b). (c, d) Levels of Q40::YFP in worms maintained on control (L4440), ash-2 or set-2 RNAi were assessed by western blot (c) and quantified by densitometry (d). (e, f) Q40::YFP expressing C. elegans strain AM141 was maintained on control (L4440), ash-2 or set-2 RNAi and Q40::YFP aggregates were examined 96 h after egg lay (that is, day 1 of adulthood) by fluorescence microscopy (e) and quantified (f). Each symbol represents an individual worm and at least 30 animals were assessed per condition. (g, h) Wild-type or set-2 (ok592) Q40::YFP C. elegans were examined 96 h after egg lay (that is, day 1 of adulthood) by fluorescence microscopy (g) and aggregates were quantified (h). Differences in relative aggregate number between (e, f) and (g, h) is likely due to the differences in the bacterial strains (RNAi strain L4440 versus OP50) used as food source. Each symbol represents an individual worm. At least 30 animals were assessed per condition. Results are representative (a, c, e, g) or the average ± SEM (graphs in b, d) of four (e, f), six (c, d), three (a, b L4440 and ash-2) or two (a, b; set-2) independent experiments. Statistical significance was assessed by one-way ANOVA (b, d), Kruskal-Wallis (f), or two-tailed Mann-Whitney (h); ****, p < 0.0001. Scale bar = 0.1 mm.

Source data

Extended Data Fig. 2 H3K4me3 modifier depletion does not enhance heat shock gene expression under non-stress conditions (related to Fig. 2).

(a) Fluorescence images of day 1 adult hsp-16.2p::GFP expressing worms maintained on control (L4440), ash-2 or set-2 RNAi before and following heat shock (HS). Scale bar is 0.1 mm. (b) Quantification of the fluorescence in individual worms (symbols) shown in (a). At least 20 animals assessed per condition. (c) Knockdown efficiency of ash-2 and hsf-1 in day 1 adult Q40::YFP animals maintained on L4440, ash-2, hsf- 1, or ash-2 + hsf-1 RNAi. (d) Paralysis of Q40::YFP animals maintained on L4440, set-2, hsf-1, or set-2 + hsf-1 RNAi. (e) Quantification of HSP-16.2::mCherry fluorescence in the heads of hsp-16.2p::hsp-16.2::mCherry-expressing Q40::YFP animals aged to day 5 of adult- hood at 20 °C on control (L4440), ash-2 or set-2 RNAi. At least 10 animals assessed per condition. (f) Steady state expression of heat shock genes hsp-16.11, hsp-16.2, hsp-16.48 in Q40::YFP animals maintained on control (L4440), ash-2 or set-2 RNAi as determined by RT-PCR. Results are representative (a, b, d, e) or the average (c, f) of two (d, e) or three or more (a-c, f) independent experiments. Error bars represent SEM. Statistical significance was determined by Kruskal-Wallis (b, f), one-way ANOVA (c, e) or log-rank (d); p < 0.05, *; p < 0.0001, ****. Additional experimental information, and data for biological replicates not shown can be found in Supplementary Table 1.

Extended Data Fig. 3 Oleic acid does not activate or potentiate the heat shock response (related to Fig. 3).

(a) CB1402 (unc-15(e1402)) worms expressing paramyosin(ts) were maintained on L4440 or hsf- 1 RNAi ± oleic acid (0.8 mM) at 15 °C. On day 1 of adulthood, animals were shifted to 25 °C, and motility was assessed 24 h later by thrashing assay. (b) Q40::YFP animals were maintained on NGM plates in the absence of supplements or in the presence of oleic acid (0.8 mM) or linoleic acid (0.8 mM). Paralysis was measured as described before. (c, d) L4 or (e, f) day 1 adults expressing the hsp-16.2p::GFP reporter were maintained on control RNAi (L4440) in the absence or presence of 0.8 mM oleic acid. Worms were either left untreated or subjected to heat shock (HS) treatment (35 °C for 2 h, 20° for 2 h). Fluorescence images were taken (c, e) and quantified (d, f). At least 25 animals were assessed per condition. Scale bar is 0.1 mm. Results are representative of four (a) or three (b-f) independent experiments. Statistical significance was assessed by χ2 test (a), Kruskal-Wallis test (c, e), and log-rank (f); *, p < 0.05; **, p < 0.01; ****, p < 0.0001. Additional experimental information, and data for biological replicates not shown, can be found in Supplementary Table 1.

Extended Data Fig. 4 Effects of H3K4me3 modifier or hsf-1 depletion and oleic acid supplementation on lipid ontology enrichment and lipid droplet formation (related to Fig. 4).

(a) Mass spectrometry analysis of lipid levels in Q40::YFP animals maintained on L4440, ash-2, hsf-1, or ash-2 + hsf-1 RNAi was conducted, and significantly altered lipids between indicated conditions were analyzed for ontology enrichment using LION/web analysis. Enriched categories in lipids that increased in each comparison are shown in red, and lipids that decreased in each comparison shown in blue, with statistically significant categories being color-coded by –log(FDR q-value). (b) Changes in saturated, monounsaturated, and polyunsaturated fatty acids in phospholipids in day 1 adult Q40::YFP worms maintained on L4440, ash-2, hsf-1, ash-2 + hsf-1 in the absence or presence of oleic acid (0.8 mM). (c, d) LIU1 (dhs-3p::dhs-3::GFP) lipid droplet reporter animals were maintained on control (L4440), ash-2, hsf-1, or ash-2 + hsf-1 RNAi, and fluorescence was imaged at day 1 (c) and day 5 (d) of adulthood. Representative images are shown. Scale bar is 0.1 mm. (e) Quantification of the dhs-3p::dhs-3::GFP fluorescence in (d). (f) mRNA levels of hsp-16.2 and hsf-1 in day 10 adult Q40::YFP worms maintained on L4440 or ash-2 RNAi. (g) Fluorescence of day 10 adult LIU1 (dhs-3p::dhs-3::GFP) animals maintained on L4440 or ash-2 RNAi. Fluorescence is quantified in (h). At least 20 animals assessed per condition. Results are representative of at least three independent experiments. Error bars represent SEM. Statistical significance was assessed by one-way ANOVA (e), one sample, two-tailed t-test (f) or Kruskal-Wallis test (h); ***, p < 0.001; ****, p < 0.0001.

Extended Data Fig. 5 hsf-1 knockdown alters genes involved in lipid synthesis and breakdown (related to Fig. 5).

(a) Differentially expressed genes in day 1 adult Q40::YFP worms maintained on hsf-1 RNAi vs L4440 control RNAi were analyzed for metabolic pathway enrichment (see methods). Significant categories are color-coded by p-value. (b) Q40::YFP worms maintained on L4440 or hsf-1 RNAi, and accumulation of acdh-1 was assessed by qPCR. Levels of the housekeeping gene pmp-3 were used as a control for normalization. (c) Q40::YFP animals were maintained on L4440 or hsf-1 RNAi in the presence or absence of oleic acid (0.8 mM) until day 1 of adulthood. Worm motility was determined by assessing animal thrashing rate following placement in a drop of M9. (d) OCR was assessed in day 5 adult Q40::YFP worms supplemented with oleic acid (0.8 mM) or maintained on ash-2 RNAi. (e) Changes in genes involved in fatty acid synthesis and breakdown in Q40::YFP worms deficient in hsf-1. Genes with statistically significant differences vs L4440 control are listed in bold. Results are the average (a, e), representative (c) or average ± SEM (b, d) of two (c), three (d), or four (a, b, e) independent experiments. Statistical significance was assessed by one-way ANOVA (B-D); *, p < 0.05; ****, p < 0.0001. Additional experimental information on RNAseq analysis can be found in Supplementary Table 3.

Extended Data Fig. 6 Working model.

Proposed mechanism by which early-in-life inactivation of H3K4me3-modifiers protects against proteotoxicity later in life. Depletion of H3K4me3 leads to the upregulation of HSF-1 activity, which is essential for the protective effect displayed by H3K4me3-deficient worms. HSF-1 activity is required for the upregulation of FAT-7, an enzyme which converts stearic acid into oleic acid, a protective mono-unsaturated fatty acid (MUFA). Although production of oleic acid is necessary for the observed protection, it’s presence is insufficient to delay the onset of amyloid toxicity. HSF-1 mediated stimulation of mitochondrial β-oxidation is required to fully protect against amyloid-mediated paralysis. Previous studies and our work showed that the activities of H3K4me3-modifiers, HSF-1 and FAT-7 in early life are directly linked to their protective effects later in life. It remains to be tested precisely how changes in lipid homeostasis protect against proteotoxicity.

Supplementary information

Reporting Summary

Supplementary Table 1

Detailed source and statistical information for all paralysis and lifespan assays.

Supplementary Table 2

Source data for all panels related to lipidomics.

Supplementary Table 3

Source data for all panels related to RNA-seq.

Supplementary Table 4

Statistical information on reproducibility and blinding for experiments.

Source data

Source Data Extended Data Fig. 1

Full western blot for Aβ blot in Extended Data Fig. 1a.

Source Data Extended Data Fig. 1

Full western blot for H3 blot in Extended Data Fig. 1a.

Source Data Extended Data Fig. 1

Full western blot for Q40::YFP and H3 blot in Extended Data Fig. 1c.

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Oleson, B.J., Bhattrai, J., Zalubas, S.L. et al. Early life changes in histone landscape protect against age-associated amyloid toxicities through HSF-1-dependent regulation of lipid metabolism. Nat Aging 4, 48–61 (2024). https://doi.org/10.1038/s43587-023-00537-4

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