Zinc finger transcription factors displaced SREBP proteins as the major Sterol regulators during Saccharomycotina evolution.
In most eukaryotes, including the majority of fungi, expression of sterol biosynthesis genes is regulated by Sterol-Regulatory Element Binding Proteins (SREBPs), which are basic helix-loop-helix transcription activators. However, in yeasts such as Saccharomyces cerevisiae and Candida albicans sterol synthesis is instead regulated by Upc2, an unrelated transcription factor with a Gal4-type zinc finger. The SREBPs in S. cerevisiae (Hms1) and C. albicans (Cph2) have lost a domain, are not major regulators of sterol synthesis, and instead regulate filamentous growth. We report here that rewiring of the sterol regulon, with Upc2 taking over from SREBP, likely occurred in the common ancestor of all Saccharomycotina. Yarrowia lipolytica, a deep-branching species, is the only genome known to contain intact and full-length orthologs of both SREBP (Sre1) and Upc2. Deleting YlUPC2, but not YlSRE1, confers susceptibility to azole drugs. Sterol levels are significantly reduced in the YlUPC2 deletion. RNA-seq analysis shows that hypoxic regulation of sterol synthesis genes in Y. lipolytica is predominantly mediated by Upc2. However, YlSre1 still retains a role in hypoxic regulation; growth of Y. lipolytica in hypoxic conditions is reduced in a Ylupc2 deletion and is abolished in a Ylsre1/Ylupc2 double deletion, and YlSre1 regulates sterol gene expression during hypoxia adaptation. We show that YlSRE1, and to a lesser extent YlUPC2, are required for switching from yeast to filamentous growth in hypoxia. Sre1 appears to have an ancestral role in the regulation of filamentation, which became decoupled from its role in sterol gene regulation by the arrival of Upc2 in the Saccharomycotina.
UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
Sarah L
SL
Maguire
UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
Can
C
Wang
UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
Linda M
LM
Holland
INRA UMR1319 Micalis, AgroParisTech, Jouy-en-Josas, France ; CNRS, Micalis, Jouy-en-Josas, France.
François
F
Brunel
INRA UMR1319 Micalis, AgroParisTech, Jouy-en-Josas, France ; CNRS, Micalis, Jouy-en-Josas, France.
Cécile
C
Neuvéglise
INRA UMR1319 Micalis, AgroParisTech, Jouy-en-Josas, France ; CNRS, Micalis, Jouy-en-Josas, France.
Jean-Marc
JM
Nicaud
University of Missouri-Kansas City, School of Biological Sciences, Cell Biology and Biophysics, Kansas City, Missouri, United States of America.
Martin
M
Zavrel
University of Missouri-Kansas City, School of Biological Sciences, Cell Biology and Biophysics, Kansas City, Missouri, United States of America.
Theodore C
TC
White
UCD School of Medicine and Medical Science, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
Kenneth H
KH
Wolfe
UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
Geraldine
G
Butler
D000595:Amino Acid Sequence; D051792:Basic Helix-Loop-Helix Proteins; D002176:Candida albicans / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D005656:Fungal Proteins; D015966:Gene Expression Regulation, Fungal; D011401:Promoter Regions, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics* / Q000378:metabolism; D013261:Sterols / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025062:Yarrowia / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics*
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D029701:Saccharomyces cerevisiae Proteins; D051779:Sterol Regulatory Element Binding Proteins; D013261:Sterols; D015534:Trans-Activators; D014157:Transcription Factors; C435125:CPH2 protein, Candida albicans; C113958:UPC2 protein, S cerevisiae