Repressive gene regulation synchronizes development with cellular metabolism

Abstract

Metabolic conditions affect the developmental tempo of most animal species. Consequently, developmental gene regulatory networks (GRNs) must faithfully adjust their dynamics to a variable time scale. We find evidence that layered weak repression of genes provides the necessary coupling between GRN output and cellular metabolism. Using a mathematical model that replicates such a scenario, we find that lowering metabolism corrects developmental errors that otherwise occur when different layers of repression are lost. Through mutant analysis, we show that gene expression dynamics are unaffected by loss of repressors, but only when cellular metabolism is reduced. We further show that when metabolism is lowered, formation of a variety of sensory organs in Drosophila is normal despite loss of individual repressors of transcription, mRNA stability, and protein stability. We demonstrate the universality of this phenomenon by experimentally eliminating the entire microRNA family of repressors, and find that all microRNAs are rendered unnecessary when metabolism is reduced. Thus, layered weak repression provides robustness through error frequency suppression, and may provide an evolutionary route to a shorter reproductive cycle.Reduced glucose consumption by cells might not only limit ATP fluxes, but also hinder the synthesis of nucleotide and amino acid precursors required for RNA and protein synthesis. To simulate this scenario, we specifically reduced the rate parameters ! 13 ! 14 ! 15 ! 16 ! 17

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