H3K9me1/2 methylation limits the lifespan of daf-2 mutants in C. elegans

  1. Meng Huang
  2. Minjie Hong
  3. Xinhao Hou
  4. Chengming Zhu
  5. Di Chen  Is a corresponding author
  6. Xiangyang Chen  Is a corresponding author
  7. Shouhong Guang  Is a corresponding author
  8. Xuezhu Feng  Is a corresponding author
  1. University of Science and Technology of China, China
  2. 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

  1. Meng Huang

    Department of Obstetrics and Gynecology, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Minjie Hong

    Department of Obstetrics and Gynecology, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Xinhao Hou

    Department of Obstetrics and Gynecology, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Chengming Zhu

    Department of Obstetrics and Gynecology, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Di Chen

    State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China
    For correspondence
    chendi@nju.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0514-7947
  6. Xiangyang Chen

    Department of Obstetrics and Gynecology, University of Science and Technology of China, Hefei, China
    For correspondence
    xychen91@ustc.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  7. Shouhong Guang

    Department of Obstetrics and Gynecology, University of Science and Technology of China, Hefei, China
    For correspondence
    sguang@ustc.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7700-9634
  8. Xuezhu Feng

    Department of Obstetrics and Gynecology, University of Science and Technology of China, Hefei, China
    For correspondence
    fengxz@ustc.edu.cn
    Competing interests
    The authors declare that no competing interests exist.

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.

Reviewing Editor

  1. Scott F Leiser, University of Michigan, United States

Version history

  1. Received: October 18, 2021
  2. Preprint posted: October 28, 2021 (view preprint)
  3. Accepted: September 16, 2022
  4. Accepted Manuscript published: September 20, 2022 (version 1)
  5. Version of Record published: September 27, 2022 (version 2)

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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  1. Meng Huang
  2. Minjie Hong
  3. Xinhao Hou
  4. Chengming Zhu
  5. Di Chen
  6. Xiangyang Chen
  7. Shouhong Guang
  8. Xuezhu Feng
(2022)
H3K9me1/2 methylation limits the lifespan of daf-2 mutants in C. elegans
eLife 11:e74812.
https://doi.org/10.7554/eLife.74812

Share this article

https://doi.org/10.7554/eLife.74812

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