SREBP Regulates Anaerobic Gene Expression in Fission Yeast

Cholesterol and fatty acid synthesis in mammals are controlled by SREBPs, a family of membrane‐bound transcription factors. Our studies identified homologs of SREBP and its binding partner SCAP in Schizosaccharomyces pombe , named sre1 + and scp1 + . Like SREBP, Sre1 is cleaved and activated in response to sterol depletion in a Scp1‐dependent manner. Sre1 is required for anaerobic growth and is rapidly activated in response to oxygen depletion. Microarray analysis reveals that Sre1 is a principal activator of anaerobic gene expression, controlling non‐respiratory, oxygen consumptive pathways such as ergosterol, heme, sphingolipid, and ubiquinone biosynthesis. Low oxygen induction of glycolytic genes and repression of mitochondrial oxidative phosphorylation genes largely does not require Sre1. Using chromatin immunoprecipitation, we demonstrated that Sre1 acts directly at promoters of target genes and stimulates its own transcription under anaerobic conditions. Promoter analysis of sre1 + identified a DNA element required for oxygen‐dependent, Sre1‐dependent transcription in vivo that is homologous to the sterol regulatory element (SRE) from the human LDL receptor promoter. Sre1 bound to both SREs in vitro highlighting the evolutionary conservation between Sre1 and SREBP. Based on these findings, we conclude that Sre1 and Scp1 monitor oxygen‐dependent sterol synthesis as an indirect measure of oxygen supply and mediate a hypoxic response in fission yeast. This mechanism represents a new paradigm for oxygen sensing in eukaryotes. This research was funded by grants from the NIH (HL‐77588) and Burroughs Wellcome Fund.