The nutrient-sensing GCN2 signaling pathway is essential for circadian clock function by regulating histone acetylation under amino acid starvation

  1. Xiao-Lan Liu
  2. Yulin Yang
  3. Yue Hu
  4. Jingjing Wu
  5. Chuqiao Han
  6. Qiaojia Lu
  7. Xihui Gan
  8. Shaohua Qi
  9. Jinhu Guo
  10. Qun He
  11. Yi Liu
  12. Xiao Liu  Is a corresponding author
  1. Chinese Academy of Sciences, China
  2. Yunnan University, China
  3. Sun Yat-sen University, China
  4. China Agricultural University, China
  5. The University of Texas Southwestern Medical Center, United States

Abstract

Circadian clocks are evolved to adapt to the daily environmental changes under different conditions. The ability to maintain circadian clock functions in response to various stresses and perturbations is important for organismal fitness. Here, we show that the nutrient-sensing GCN2 signaling pathway is required for robust circadian clock function under amino acid starvation in Neurospora. The deletion of GCN2 pathway components disrupts rhythmic transcription of clock gene frq by suppressing WC complex binding at the frq promoter due to its reduced histone H3 acetylation levels. Under amino acid starvation, the activation of GCN2 kinase and its downstream transcription factor CPC-1 establish a proper chromatin state at the frq promoter by recruiting the histone acetyltransferase GCN-5. The arrhythmic phenotype of the GCN2 kinase mutants under amino acid starvation can be rescued by inhibiting histone deacetylation. Finally, genome-wide transcriptional analysis indicates that the GCN2 signaling pathway maintains robust rhythmic expression of metabolic genes under amino acid starvation. Together, these results uncover an essential role of the GCN2 signaling pathway in maintaining the robust circadian clock function in response to amino acid starvation, and demonstrate the importance of histone acetylation at the frq locus in rhythmic gene expression.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Our generated RNA Sequencing data have been deposited in GEO under accession code GSE220169.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Xiao-Lan Liu

    Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1755-3387
  2. Yulin Yang

    Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Yue Hu

    Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Jingjing Wu

    Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Chuqiao Han

    School of Life Sciences, Yunnan University, Kunming, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Qiaojia Lu

    Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Xihui Gan

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Shaohua Qi

    College of Biological Sciences, China Agricultural University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Jinhu Guo

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Qun He

    College of Biological Sciences, China Agricultural University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Yi Liu

    Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8801-9317
  12. Xiao Liu

    Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    For correspondence
    liux@im.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6053-132X

Funding

National Natural Science Foundation of China (32170092)

  • Xiao Liu

National Institutes of Health (R35 GM118118)

  • Yi Liu

Welch Foundation (I-1560)

  • Yi Liu

National Natural Science Foundation of China (31970079)

  • Xiao Liu

National Key Research and Development Program of China (2021YFA0911300)

  • Xiao Liu

Strategic Priority Research Program of the Chinese Academy of Sciences (XDA28030402)

  • Xiao Liu

Beijing Natural Science Foundation (5202020)

  • Xiao Liu

CAS Interdisciplinary Innovation Team

  • Xiao Liu

National Natural Science Foundation of China (32200056)

  • Xiao-Lan Liu

National Key Research and Development Program of China (2018YFA0900500)

  • Qun He

National Natural Science Foundation of China (32170560)

  • Qun He

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

Reviewing Editor

  1. Alan G Hinnebusch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States

Version history

  1. Received: November 29, 2022
  2. Preprint posted: December 12, 2022 (view preprint)
  3. Accepted: April 20, 2023
  4. Accepted Manuscript published: April 21, 2023 (version 1)
  5. Version of Record published: May 17, 2023 (version 2)

Copyright

© 2023, Liu 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. Xiao-Lan Liu
  2. Yulin Yang
  3. Yue Hu
  4. Jingjing Wu
  5. Chuqiao Han
  6. Qiaojia Lu
  7. Xihui Gan
  8. Shaohua Qi
  9. Jinhu Guo
  10. Qun He
  11. Yi Liu
  12. Xiao Liu
(2023)
The nutrient-sensing GCN2 signaling pathway is essential for circadian clock function by regulating histone acetylation under amino acid starvation
eLife 12:e85241.
https://doi.org/10.7554/eLife.85241

Share this article

https://doi.org/10.7554/eLife.85241

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