Sugar-responsive inhibition of Myc-dependent ribosome biogenesis by Clockwork orange

Cell Rep. 2023 Jul 25;42(7):112739. doi: 10.1016/j.celrep.2023.112739. Epub 2023 Jul 4.


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.

Keywords: CP: Molecular biology; Drosophila; hepatocyte; metabolism; nutrient sensing; ribosome biogenesis; sugar; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drosophila / metabolism
  • Drosophila Proteins* / metabolism
  • Mice
  • Repressor Proteins* / metabolism
  • Ribosomes* / metabolism
  • Sugars* / metabolism
  • Transcription Factors / metabolism


  • Drosophila Proteins
  • Sugars
  • Transcription Factors
  • Cwo protein, Drosophila
  • Repressor Proteins