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

Xiao Lan Liu, Yulin Yang, Yue Hu, Jingjing Wu, Chuqiao Han, Qiaojia Lu, Xihui Gan, Shaohua Qi, Jinhu Guo, Qun He, Yi Liu, Xiao Liu

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
JournaleLife
Volume12
DOIs
StatePublished - Apr 21 2023

Keywords

  • CPC-3/CPC-1 pathway
  • N. crassa
  • Neurospora crassa
  • amino acid starvation
  • cell biology
  • circadian rhythm
  • genetics
  • genomics
  • histone acetylation

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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