Nutritional compensation of the circadian clock is a conserved process influenced by gene expression regulation and mRNA stability
Year: 2023
Type: article
Abstract: Compensation is a defining principle of a true circadian clock, where its approximately 24-hour period length is relatively unchanged across environmental conditions. Known compensation effectors directly regulate core clock factors to buffer the oscillator's period length from variables in the environment. Temperature Compensation mechanisms have been experimentally addressed across circadian model systems, but much less is known about the related process of Nutritional Compensation, where circadian period length is maintained across physiologically relevant nutrient levels. Using the filamentous fungus Neurospora crassa, we performed a genetic screen under glucose and amino acid starvation conditions to identify new regulators of Nutritional Compensation. Our screen uncovered 16 novel mutants, and together with 4 mutants characterized in prior work, a model emerges where Nutritional Compensation of the fungal clock is achieved at the levels of transcription, chromatin regulation, and mRNA stability. However, eukaryotic circadian Nutritional Compensation is completely unstudied outside of Neurospora. To test for conservation in cultured human cells, we selected top hits from our fungal genetic screen, performed siRNA knockdown experiments of the mammalian orthologs, and characterized the cell lines with respect to compensation. We find that the wild-type mammalian clock is also compensated across a large range of external glucose concentrations, as observed in Neurospora, and that knocking down the mammalian orthologs of the Neurospora compensation-associated genes CPSF6 or SETD2 in human cells also results in nutrient-dependent period length changes. We conclude that, like Temperature Compensation, Nutritional Compensation is a conserved circadian process in fungal and mammalian clocks and that it may share common molecular determinants.
Source: PLoS Biology
Institutions: Dartmouth College, University of Massachusetts Boston
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,500
Funders: National Science Foundation, Memorial Sloan-Kettering Cancer Center, Cincinnati Children's Hospital Medical Center, Dartmouth College, University of South Florida, Pontificia Universidad Católica de Chile, National Institutes of Health, Audrey and Theodor Geisel School of Medicine at Dartmouth, National Cancer Institute, National Institute of General Medical Sciences
Awards: Functional Analysis and Systems Biology of Filamentous Fungi, G1830523874, G2289115564, G2597928684, G3176204732, Identification and Analysis of Circadian Clock-Controlled Genes, Genetic and Molecular Dissection of Regulatory Mechanisms Underlying Temperature and Nutritional Compensation of the Circadian Clock in Neurospora crassa, G4689626916, G6114118680, G6898742010, G9000053803, Cancer Center Support Grant, Center for Quantitative Biology: A focus on "omics", from organisms to single cells, Genetic and Molecular Dissection of the Neurospora Clock
OpenAlex ID: W4313543593