Epigenetic drift of H3K27me3 in aging links glycolysis to healthy longevity in Drosophila

  1. Zaijun Ma
  2. Hui Wang
  3. Yuping Cai
  4. Han Wang
  5. Kongyan Niu
  6. Xiaofen Wu
  7. Huanhuan Ma
  8. Yun Yang
  9. Wenhua Tong
  10. Feng Liu
  11. Zhandong Liu
  12. Yaoyang Zhang
  13. Rui Liu
  14. Zheng-Jiang Zhu  Is a corresponding author
  15. Nan Liu  Is a corresponding author
  1. Chinese Academy of Sciences, China
  2. Shanghai Jiao Tong University School of Medicine, China
  3. Texas Children's Hospital, United States
  4. Singlera Genomics, China

Abstract

Epigenetic alteration has been implicated in aging. However, the mechanism by which epigenetic change impacts aging remains to be understood. H3K27me3, a highly conserved histone modification signifying transcriptional repression, is marked and maintained by Polycomb Repressive Complexes (PRCs). Here, we explore the mechanism by which age-modulated increase of H3K27me3 impacts adult lifespan. Using Drosophila, we reveal that aging leads to loss of fidelity in epigenetic marking and drift of H3K27me3 and consequential reduction in the expression of glycolytic genes with negative effects on energy production and redox state. We show that a reduction of H3K27me3 by PRCs-deficiency promotes glycolysis and healthy lifespan. While perturbing glycolysis diminishes the pro-lifespan benefits mediated by PRCs-deficiency, transgenic increase of glycolytic genes in wild-type animals extends longevity. Together, we propose that epigenetic drift of H3K27me3 is one of the molecular mechanisms that contribute to aging and that stimulation of glycolysis promotes metabolic health and longevity.

Data availability

The raw data files of sequencing experiments have been deposited in the NCBI Gene Expression Omnibus, as well as the normalized read density profiles of ChIP-seq and differential expression results from DESeq of RNA-seq reported in this paper. The accession number is GEO: GSE96654.

The following data sets were generated

Article and author information

Author details

  1. Zaijun Ma

    Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    No competing interests declared.
  2. Hui Wang

    Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3522-0164
  3. Yuping Cai

    Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    No competing interests declared.
  4. Han Wang

    Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    No competing interests declared.
  5. Kongyan Niu

    Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    No competing interests declared.
  6. Xiaofen Wu

    Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    No competing interests declared.
  7. Huanhuan Ma

    Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    No competing interests declared.
  8. Yun Yang

    Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    No competing interests declared.
  9. Wenhua Tong

    Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    No competing interests declared.
  10. Feng Liu

    State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    Competing interests
    No competing interests declared.
  11. Zhandong Liu

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    No competing interests declared.
  12. Yaoyang Zhang

    Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    No competing interests declared.
  13. Rui Liu

    Singlera Genomics, Shanghai, China
    Competing interests
    Rui Liu, is affiliated with Singlera Genomics, a company providing customized next generation sequencing services. The author has no financial interests to declare.
  14. Zheng-Jiang Zhu

    Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, Shanghai, China
    For correspondence
    jiangzhu@sioc.ac.cn
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3272-3567
  15. Nan Liu

    Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, Shanghai, China
    For correspondence
    liunan@sioc.ac.cn
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7384-0794

Funding

National Program on Key Research Projects of China (2016YFA0501900)

  • Nan Liu

National Science Foundation of China (31371326)

  • Nan Liu

National Science Foundation of China (31671428)

  • Yaoyang Zhang

National Science Foundation of China (31500665)

  • Yaoyang Zhang

National Science Foundation of China (31530041)

  • Yaoyang Zhang

National Science Foundation of China (81770143)

  • Feng Liu

National Institutes of Health (GM120033)

  • Zhandong Liu

National Science Foundation (DMS-1263932)

  • Zhandong Liu

Cancer Prevention and Research Institute of Texas (RP170387)

  • Zhandong Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Matt Kaeberlein, University of Washington, United States

Version history

  1. Received: January 24, 2018
  2. Accepted: April 23, 2018
  3. Accepted Manuscript published: May 29, 2018 (version 1)
  4. Version of Record published: June 7, 2018 (version 2)
  5. Version of Record updated: October 11, 2018 (version 3)

Copyright

© 2018, Ma 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

  • 8,266
    views
  • 1,159
    downloads
  • 85
    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. Zaijun Ma
  2. Hui Wang
  3. Yuping Cai
  4. Han Wang
  5. Kongyan Niu
  6. Xiaofen Wu
  7. Huanhuan Ma
  8. Yun Yang
  9. Wenhua Tong
  10. Feng Liu
  11. Zhandong Liu
  12. Yaoyang Zhang
  13. Rui Liu
  14. Zheng-Jiang Zhu
  15. Nan Liu
(2018)
Epigenetic drift of H3K27me3 in aging links glycolysis to healthy longevity in Drosophila
eLife 7:e35368.
https://doi.org/10.7554/eLife.35368

Share this article

https://doi.org/10.7554/eLife.35368

Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Lucie Crhak Khaitova, Pavlina Mikulkova ... Karel Riha
    Research Article

    Heat stress is a major threat to global crop production, and understanding its impact on plant fertility is crucial for developing climate-resilient crops. Despite the known negative effects of heat stress on plant reproduction, the underlying molecular mechanisms remain poorly understood. Here, we investigated the impact of elevated temperature on centromere structure and chromosome segregation during meiosis in Arabidopsis thaliana. Consistent with previous studies, heat stress leads to a decline in fertility and micronuclei formation in pollen mother cells. Our results reveal that elevated temperature causes a decrease in the amount of centromeric histone and the kinetochore protein BMF1 at meiotic centromeres with increasing temperature. Furthermore, we show that heat stress increases the duration of meiotic divisions and prolongs the activity of the spindle assembly checkpoint during meiosis I, indicating an impaired efficiency of the kinetochore attachments to spindle microtubules. Our analysis of mutants with reduced levels of centromeric histone suggests that weakened centromeres sensitize plants to elevated temperature, resulting in meiotic defects and reduced fertility even at moderate temperatures. These results indicate that the structure and functionality of meiotic centromeres in Arabidopsis are highly sensitive to heat stress, and suggest that centromeres and kinetochores may represent a critical bottleneck in plant adaptation to increasing temperatures.

    1. Cell Biology
    Wan-ping Yang, Mei-qi Li ... Qian-qian Luo
    Research Article

    High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic conditions. The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen’s ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.