Zinc finger transcription factors displaced SREBP proteins as the major sterol regulators during Saccharomycotina evolution
All but a few eukaryotes die without oxygen and respond dynamically to changes in the level of oxygen available to them. One ancient oxygen-requiring biochemical pathway in eukaryotes is the pathway for the biosynthesis of sterols, leading to cholesterol in animals and ergosterol in fungi. Mutations in this pathway are a frequent cause of azole drug resistance in pathogenic fungi. The regulatory mechanism for the sterol pathway is also widely conserved between animals and fungi and is centred on a transcription activator, SREBP, that forms part of a sterol-sensing complex. However, in one group of yeasts – the Saccharomycotina, which includes the major pathogen Candida albicans – control of the sterol pathway has been taken over by an unrelated regulatory protein, Upc2. We show here by analysis of the yeast Yarrowia lipolytica that the evolutionary switch from SREBP to Upc2 was a two-step process in which Upc2 appeared in an ancestor of Saccharomycotina, and SREBP subsequently degenerated and lost its sterol-regulatory function while retaining an ancient role in filamentation. Overall design: RNA was isolated from Y. lipolytica wildtype (JMY2900) in normoxia (21% oxygen, 4 biological replicates),  wildtype (JMY2900) in hypoxia (1% oxygen, 5 biological replicates),  upc2 deletion (SMY2) in hypoxia (1% oxygen, 3 biological replicates), and from  sre1 (SMY5, SMY8) deletion in hypoxia (1% oxygen, 2 biological replicates). Gene expression was determined using strand-specific RNA-seq.