Abstract
BackgroundOptimal glucose metabolism is central to the growth and development of cells. In microbial eukaryotes, carbon catabolite repression (CCR) mediates the preferential utilization of glucose, primarily by repressing alternate carbon source utilization. In fission yeast, CCR is mediated by transcriptional repressors Scr1 and the Tup/Ssn6 complex, with the Rst2 transcription factor important for activation of gluconeogenesis and sexual differentiation genes upon derepression. Through genetic and genome-wide methods, this study aimed to comprehensively characterize CCR in fission yeast by identifying the genes and biological processes that are regulated by Scr1, Tup/Ssn6 and Rst2, the core CCR machinery.ResultsThe transcriptional response of fission yeast to glucose-sufficient or glucose-deficient growth conditions in wild type and CCR mutant cells was determined by RNA-seq and ChIP-seq. Scr1 was found to regulate genes involved in carbon metabolism, hexose uptake, gluconeogenesis and the TCA cycle. Surprisingly, a role for Scr1 in the suppression of sexual differentiation was also identified, as homothallic scr1 deletion mutants showed ectopic meiosis in carbon and nitrogen rich conditions. ChIP-seq characterised the targets of Tup/Ssn6 and Rst2 identifying regulatory roles within and independent of CCR. Finally, a subset of genes bound by all three factors was identified, implying that regulation of certain loci may be modulated in a competitive fashion between the Scr1, Tup/Ssn6 repressors and the Rst2 activator.ConclusionsBy identifying the genes directly and indirectly regulated by Scr1, Tup/Ssn6 and Rst2, this study comprehensively defined the gene regulatory networks of CCR in fission yeast and revealed the transcriptional complexities governing this system.
Highlights
Optimal glucose metabolism is central to the growth and development of cells
We examined key carbon metabolism pathways in further detail, confirming widespread upregulation of almost all carbon metabolism genes examined in glucose-deficient conditions, while glycolysis and fermentation genes were repressed under glucose-starved conditions (Additional file 1: Figure S3)
We found that Scr1 is replaced by Rst2 in glucose-starved conditions at carbon catabolite repression (CCR) genes that show Tup11 enrichment, increased expression and increased RNA Pol IISer5 enrichment compared to glucose-sufficient conditions, supporting the hypothesis that Tup/Ssn6 function can be toggled between repressing and activating functions via association with different transcription factors (Fig. 8)
Summary
Optimal glucose metabolism is central to the growth and development of cells. In microbial eukaryotes, carbon catabolite repression (CCR) mediates the preferential utilization of glucose, primarily by repressing alternate carbon source utilization. CCR is mediated by transcriptional repressors Scr and the Tup/Ssn complex, with the Rst transcription factor important for activation of gluconeogenesis and sexual differentiation genes upon derepression. Schizosaccharomyces pombe, CCR is mediated by Scr, a conserved C2H2 zinc finger transcriptional repressor orthologous to the well characterized Saccharomyces cerevisiae Mig and Aspergillus nidulans CreA [4]. Vassiliadis et al BMC Genomics (2019) 20:251 transcription factors co-localise with additional transcriptional machinery, such as the conserved Tup/Ssn complex, which is required to establish full transcriptional repression of CCR regulated genes [7,8,9]. In S. pombe and S. cerevisiae, this occurs via AMP-activated protein kinase (AMPK) mediated phosphorylation of Scr1/Mig upon glucose depletion, which dissociates these transcription factors from chromatin and triggers their nuclear export [16, 17]
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