H3K9me1/2 methylation limits the lifespan of daf-2 mutants in C. elegans
- University of Science and Technology of China, China
- Nanjing University, China
Abstract
Histone methylation plays crucial roles in the development, gene regulation and maintenance of stem cell pluripotency in mammals. Recent work shows that histone methylation is associated with aging, yet the underlying mechanism remains unclear. In this work, we identified a class of putative histone 3 lysine 9 mono-/di-methyltransferase genes (met-2, set-6, set-19, set-20, set-21, set-32 and set-33), mutations in which induce synergistic lifespan extension in the long-lived DAF-2 (IGF-1 receptor) mutant in C. elegans. These putative histone methyltransferase plus daf-2 double mutants not only exhibited an average lifespan nearly three times that of wild-type animals and a maximal lifespan of approximately 100 days, but also significantly increased resistance to oxidative and heat stress. Synergistic lifespan extension depends on the transcription factor DAF-16 (FOXO). mRNA-seq experiments revealed that the mRNA levels of DAF-16 Class I genes, which are activated by DAF-16, were further elevated in the daf-2;set double mutants. Among these genes, tts-1, F35E8.7, ins-35, nhr-62, sod-3, asm-2 and Y39G8B.7 are required for the lifespan extension of the daf-2;set-21 double mutant. In addition, treating daf-2 animals with the H3K9me1/2 methyltransferase G9a inhibitor also extends lifespan and increases stress resistance. Therefore, investigation of DAF-2 and H3K9me1/2 deficiency-mediated synergistic longevity will contribute to a better understanding of the molecular mechanisms of aging and therapeutic applications.
Data availability
Sequencing data have been deposited in GSA under accession codes CRA005256.Figure 2 - Source Data 1 and Figure 8 - Source Data 2 contain the original files and figures of the blots used to generate the figures.Source Code Files 1 is used to convert BAM files to BigWig format in ChIP-seq data analysis.
Article and author information
Author details
Funding
National Key Research and Development Program of China
- Shouhong Guang
National Natural Science Foundation of China
- Shouhong Guang
Fundamental Research Funds for the Central Universities
- Shouhong Guang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Huang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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H3K9me1/2 methylation limits the lifespan of daf-2 mutants in C. elegans
eLife 11:e74812.
https://doi.org/10.7554/eLife.74812
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