1. Chromosomes and Gene Expression
  2. Genetics and Genomics

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
https://doi.org/10.7554/eLife.74812
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

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.

Metrics

  • 2,167
    views
  • 521
    downloads
  • 12
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Categories and tags

Research organism

Further reading

    1. Chromosomes and Gene Expression

    Sir2 and Fun30 regulate ribosomal DNA replication timing via MCM helicase positioning and nucleosome occupancy

    Carmina Lichauco, Eric J Foss ... Antonio Bedalov
    Research Article

    The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA (rDNA) arrays. We have previously reported that in the absence of SIR2, a de-repressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the nondisplaced MCMs. Furthermore, we found that both activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of FUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin in vivo relies on the nucleosome context shaped by a single chromatin remodeler.

    1. Chromosomes and Gene Expression

    Cryogenic Electron Microscopy: MagIC beads for scarce macromolecules

    Carlos Moreno-Yruela, Beat Fierz
    Insight

    Specialized magnetic beads that bind target proteins to a cryogenic electron microscopy grid make it possible to study the structure of protein complexes from dilute samples.

    1. Chromosomes and Gene Expression
    2. Structural Biology and Molecular Biophysics

    Surprising features of nuclear receptor interaction networks revealed by live-cell single-molecule imaging

    Liza Dahal, Thomas GW Graham ... Xavier Darzacq
    Research Article

    Type II nuclear receptors (T2NRs) require heterodimerization with a common partner, the retinoid X receptor (RXR), to bind cognate DNA recognition sites in chromatin. Based on previous biochemical and overexpression studies, binding of T2NRs to chromatin is proposed to be regulated by competition for a limiting pool of the core RXR subunit. However, this mechanism has not yet been tested for endogenous proteins in live cells. Using single-molecule tracking (SMT) and proximity-assisted photoactivation (PAPA), we monitored interactions between endogenously tagged RXR and retinoic acid receptor (RAR) in live cells. Unexpectedly, we find that higher expression of RAR, but not RXR, increases heterodimerization and chromatin binding in U2OS cells. This surprising finding indicates the limiting factor is not RXR but likely its cadre of obligate dimer binding partners. SMT and PAPA thus provide a direct way to probe which components are functionally limiting within a complex TF interaction network providing new insights into mechanisms of gene regulation in vivo with implications for drug development targeting nuclear receptors.