Sugar-responsive inhibition of Myc-dependent ribosome biogenesis by Clockwork orange
Linda van den Berg,
Krista Kokki,
Sylvia J. Wowro,
Konstantin M. Petricek,
Onur Deniz,
Catrin A. Stegmann,
Marius Robciuc,
Mari Teesalu,
Richard G. Melvin,
Anni I. Nieminen,
Michael Schupp,
Ville Hietakangas
Affiliations
Linda van den Berg
Faculty of Biological and Environmental Sciences, University of Helsinki, 00790 Helsinki, Finland; Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, 00790 Helsinki, Finland
Krista Kokki
Faculty of Biological and Environmental Sciences, University of Helsinki, 00790 Helsinki, Finland; Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, 00790 Helsinki, Finland
Sylvia J. Wowro
Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Max Rubner Center (MRC) for Cardiovascular Metabolic Renal Research, 10117 Berlin, Germany
Konstantin M. Petricek
Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Max Rubner Center (MRC) for Cardiovascular Metabolic Renal Research, 10117 Berlin, Germany
Onur Deniz
Faculty of Biological and Environmental Sciences, University of Helsinki, 00790 Helsinki, Finland; Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, 00790 Helsinki, Finland
Catrin A. Stegmann
Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Max Rubner Center (MRC) for Cardiovascular Metabolic Renal Research, 10117 Berlin, Germany
Marius Robciuc
Faculty of Biological and Environmental Sciences, University of Helsinki, 00790 Helsinki, Finland; Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, 00790 Helsinki, Finland
Mari Teesalu
Faculty of Biological and Environmental Sciences, University of Helsinki, 00790 Helsinki, Finland; Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, 00790 Helsinki, Finland
Richard G. Melvin
School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, VIC 3083, Australia
Anni I. Nieminen
Faculty of Biological and Environmental Sciences, University of Helsinki, 00790 Helsinki, Finland; Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, 00790 Helsinki, Finland
Michael Schupp
Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Max Rubner Center (MRC) for Cardiovascular Metabolic Renal Research, 10117 Berlin, Germany
Ville Hietakangas
Faculty of Biological and Environmental Sciences, University of Helsinki, 00790 Helsinki, Finland; Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, 00790 Helsinki, Finland; Corresponding author
Summary: The ability to feed on a sugar-containing diet depends on a gene regulatory network controlled by the intracellular sugar sensor Mondo/ChREBP-Mlx, which remains insufficiently characterized. Here, we present a genome-wide temporal clustering of sugar-responsive gene expression in Drosophila larvae. We identify gene expression programs responding to sugar feeding, including downregulation of ribosome biogenesis genes, known targets of Myc. Clockwork orange (CWO), a component of the circadian clock, is found to be a mediator of this repressive response and to be necessary for survival on a high-sugar diet. CWO expression is directly activated by Mondo-Mlx, and it counteracts Myc through repression of its gene expression and through binding to overlapping genomic regions. CWO mouse ortholog BHLHE41 has a conserved role in repressing ribosome biogenesis genes in primary hepatocytes. Collectively, our data uncover a cross-talk between conserved gene regulatory circuits balancing the activities of anabolic pathways to maintain homeostasis during sugar feeding.
