Sterol Regulatory Element Binding Protein Is a Principal Regulator of Anaerobic Gene Expression in Fission Yeast

Abstract

Fission yeast sterol regulatory element binding protein (SREBP), called Sre1p, functions in an oxygensensing pathway to allow adaptation to fluctuating oxygen concentrations. The Sre1p-Scp1p complex responds to oxygen-dependent sterol synthesis as an indirect measure of oxygen availability. To examine the role of Sre1p in anaerobic gene expression in Schizosaccharomyces pombe, we performed transcriptional profiling experiments after a shift to anaerobic conditions for 1.5 h. Of the 4,940 genes analyzed, expression levels of 521 (10.5%) and 686 (13.9%) genes were significantly increased and decreased, respectively, under anaerobic conditions. Sre1p controlled 68% of genes induced >2-fold. Oxygen-requiring biosynthetic pathways for ergosterol, heme, sphingolipid, and ubiquinone were primary targets of Sre1p. Induction of glycolytic genes and repression of mitochondrial oxidative phosphorylation genes largely did not require Sre1p. Using chromatin immunoprecipitation, we demonstrated that Sre1p acts directly at target gene promoters and stimulates its own transcription under anaerobic conditions. sre1 ؉ promoter analysis identified two DNA elements that are both necessary and sufficient for oxygen-dependent, Sre1p-dependent transcription. Interestingly, these elements are homologous to sterol regulatory elements bound by mammalian SREBP, highlighting the evolutionary conservation between Sre1p and SREBP. We conclude that Sre1p is a principal activator of anaerobic gene expression, upregulating genes required for nonrespiratory oxygen consumption.

Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

“…Genome-wide gene expression studies revealed that Sre1 is principally a transcriptional activator that upregulates genes required for adaptation to hypoxia, including several oxygen-dependent enzymes in biosynthetic pathways for ergosterol, heme, and sphingolipids (Todd et al 2006). Consistent with the requirement for hypoxic gene expression, cells lacking Sre1 or Scp1 fail to grow under low oxygen.…”

“…Sre1 does not control expression of glycolytic or respiratory genes, indicating that other hypoxic transcription factors exist in S. pombe. Promoter analysis of the sre1 + gene revealed two DNA-binding sites that resembled the SRE found in the human LDL receptor promoter, and expression of Sre1 mRNA, like mammalian SREBP-2, is autoregulated in a positive feedback loop (Todd et al 2006;Sehgal et al 2007). …”

Multiple functions of ergosterol in the fission yeast Schizosaccharomyces pombe

“…Although fission yeast Erg31p and Erg32p share redundant functions, these two proteins seem to have distinct roles in ergosterol synthesis. erg31 + is induced about fourfold under anaerobic conditions, while transcription of erg32 + decreases (Todd et al, 2006). Tolerance of ergD mutants to nystatin and amphotericin B (Fig.…”

“…The observed conservation of the erg genes suggests that Schiz. pombe synthesizes ergosterol in a similar manner (Todd et al, 2006). However, there is no evidence to date that these conserved genes are truly required for ergosterol synthesis in fission yeast.…”

“…Nonetheless, genes encoding the latter part of the ergosterol biosynthetic pathway have been predicted through studies of transcriptional activation under anaerobic conditions (see Fig. 1b and Table 1 of Todd et al, 2006). It is not known whether these genes are truly involved in the ergosterol biosynthetic pathway, nor is it clear what specific defects are caused by loss of ergosterol in fission yeast.…”