Zinc finger transcription factors displaced SREBP proteins as the major sterol regulators during Saccharomycotina evolution
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ABSTRACT:
ORGANISM(S): Yarrowia lipolytica
PROVIDER: GSE47433 | GEO | 2013/11/19
SECONDARY ACCESSION(S): PRJNA205557
REPOSITORIES: GEO
Similar Datasets
Project description: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 M-bM-^@M-^S the Saccharomycotina, which includes the major pathogen Candida albicans M-bM-^@M-^S 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. 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.
2013-11-19 | E-GEOD-47433 | biostudies-arrayexpress
Project description:Sterol Regulatory Element Binding Proteins (SREBPs) are conserved from yeast to mammalian cells and function in regulating sterol homeostasis. In fungi, the SREBP pathway has been implicated in the adaptation to hypoxia and in virulence. In Neurospora crassa and Trichoderma reesei, the SREBP pathway also negatively regulates protein secretion under lignocellulolytic conditions. Here we utilized global transcriptional profiling combined with genetic and physiological analyses to address the regulatory link between the SREBP pathway and protein secretion in N. crassa. Our results demonstrated that the function of the SREBP pathway in ergosterol biosynthesis and adaptation to hypoxia was conserved in N. crassa. Under lignocellulolytic conditions, the SREBP pathway was highly activated, resulting in the reduced expression of lytic polysaccharide monooxygenases, which require molecular oxygen for catalytic activity. Additionally, activation of the SREBP pathway under lignocellulolytic conditions repressed a set of genes predicted to be involved in the ER stress response. Here we show that the inability of a hac-1 mutant, which bears a deletion of the major regulator of the unfolded protein response (UPR), to efficiently produce cellulases and utilize cellulose was suppressed by mutations in the SREBP pathway. The analyses presented here demonstrated new functions of SREBP pathway, including linkages to the UPR and provide new clues for genetic engineering of filamentous fungi to improve their production of extracellular proteins.
2017-04-11 | GSE95807 | GEO
Project description:This is a deterministic nonlinear ordinary differential equation mathematical model of the sterol regulatory element binding protein 2 (SREBP-2) cholesterol genetic regulatory pathway in a hepatocyte.
2024-09-02 | BIOMD0000000890 | BioModels
Project description:Candida albicans is associated with humans as both a harmless commensal organism and a pathogen. Cph2 is a transcription factor whose DNA binding domain is similar to mammalian sterol response element binding proteins (SREBPs). SREBPs are master regulators of cellular cholesterol levels, and are highly conserved from fungi to mammals. However, ergosterol biosynthesis is regulated by the zinc finger transcription factor Upc2 in C. albicans and several other yeasts. Cph2 is not necessary for ergosterol biosynthesis, but important for colonization in the murine gastrointestinal tract. Here we demonstrate that Cph2 is a membrane-associated transcription factor that is processed to release the N-terminal DNA binding domain like SREBPs; but its cleavage is not regulated by cellular levels of ergosterol or oxygen. ChIP-Seq shows that Cph2 binds to the promoters of HMS1 and other components of the regulatory circuit for GI tract colonization. In addition, 50% of Cph2 targets are also bound by Hms1 and other factors of the regulatory circuit. Several common targets function at the head of the glycolysis pathway. Thus, Cph2 is an integral part of the regulatory circuit for GI colonization that regulates glycolytic flux. RNA-seq shows a significant overlap in genes differentially regulated by Cph2 and hypoxia, and Cph2 is important for optimal expression of some hypoxia-responsive genes in glycolysis and the citric acid cycle. We suggest that Cph2 and Upc2 regulate hypoxia-responsive expression in different pathways, consistent with a synthetic lethal defect of the cph2 upc2 double mutant in hypoxia. Expression profiling by high throughput sequencing. RNA sequencing was performed on wild type and cph2 deletion strains. 2 biological replicates were sequenced for each strain.
2015-08-10 | E-GEOD-71902 | biostudies-arrayexpress
Project description:Candida albicans is associated with humans as both a harmless commensal organism and a pathogen. Cph2 is a transcription factor whose DNA binding domain is similar to mammalian sterol response element binding proteins (SREBPs). SREBPs are master regulators of cellular cholesterol levels, and are highly conserved from fungi to mammals. However, ergosterol biosynthesis is regulated by the zinc finger transcription factor Upc2 in C. albicans and several other yeasts. Cph2 is not necessary for ergosterol biosynthesis, but important for colonization in the murine gastrointestinal tract. Here we demonstrate that Cph2 is a membrane-associated transcription factor that is processed to release the N-terminal DNA binding domain like SREBPs; but its cleavage is not regulated by cellular levels of ergosterol or oxygen. ChIP-Seq shows that Cph2 binds to the promoters of HMS1 and other components of the regulatory circuit for GI tract colonization. In addition, 50% of Cph2 targets are also bound by Hms1 and other factors of the regulatory circuit. Several common targets function at the head of the glycolysis pathway. Thus, Cph2 is an integral part of the regulatory circuit for GI colonization that regulates glycolytic flux. RNA-seq shows a significant overlap in genes differentially regulated by Cph2 and hypoxia, and Cph2 is important for optimal expression of some hypoxia-responsive genes in glycolysis and the citric acid cycle. We suggest that Cph2 and Upc2 regulate hypoxia-responsive expression in different pathways, consistent with a synthetic lethal defect of the cph2 upc2 double mutant in hypoxia. Genome binding/occupancy profiling by high throughput sequencing. ChIP-seq of Cph2 was carried out in a wild-type strain carrying N-terminal myc-tagged Cph2 under the MAL2 promoter (MAL2-myc-Cph2N). IP and INPUT samples from 2 independent experiments, as well as a sample of untagged wild-type control, were sequenced.
2015-08-05 | E-GEOD-71728 | biostudies-arrayexpress
Project description:Candida albicans is associated with humans as both a harmless commensal organism and a pathogen. Cph2 is a transcription factor whose DNA binding domain is similar to mammalian sterol response element binding proteins (SREBPs). SREBPs are master regulators of cellular cholesterol levels, and are highly conserved from fungi to mammals. However, ergosterol biosynthesis is regulated by the zinc finger transcription factor Upc2 in C. albicans and several other yeasts. Cph2 is not necessary for ergosterol biosynthesis, but important for colonization in the murine gastrointestinal tract. Here we demonstrate that Cph2 is a membrane-associated transcription factor that is processed to release the N-terminal DNA binding domain like SREBPs; but its cleavage is not regulated by cellular levels of ergosterol or oxygen. ChIP-Seq shows that Cph2 binds to the promoters of HMS1 and other components of the regulatory circuit for GI tract colonization. In addition, 50% of Cph2 targets are also bound by Hms1 and other factors of the regulatory circuit. Several common targets function at the head of the glycolysis pathway. Thus, Cph2 is an integral part of the regulatory circuit for GI colonization that regulates glycolytic flux. RNA-seq shows a significant overlap in genes differentially regulated by Cph2 and hypoxia, and Cph2 is important for optimal expression of some hypoxia-responsive genes in glycolysis and the citric acid cycle. We suggest that Cph2 and Upc2 regulate hypoxia-responsive expression in different pathways, consistent with a synthetic lethal defect of the cph2 upc2 double mutant in hypoxia.
2015-08-10 | GSE71902 | GEO
Project description:Candida albicans is associated with humans as both a harmless commensal organism and a pathogen. Cph2 is a transcription factor whose DNA binding domain is similar to mammalian sterol response element binding proteins (SREBPs). SREBPs are master regulators of cellular cholesterol levels, and are highly conserved from fungi to mammals. However, ergosterol biosynthesis is regulated by the zinc finger transcription factor Upc2 in C. albicans and several other yeasts. Cph2 is not necessary for ergosterol biosynthesis, but important for colonization in the murine gastrointestinal tract. Here we demonstrate that Cph2 is a membrane-associated transcription factor that is processed to release the N-terminal DNA binding domain like SREBPs; but its cleavage is not regulated by cellular levels of ergosterol or oxygen. ChIP-Seq shows that Cph2 binds to the promoters of HMS1 and other components of the regulatory circuit for GI tract colonization. In addition, 50% of Cph2 targets are also bound by Hms1 and other factors of the regulatory circuit. Several common targets function at the head of the glycolysis pathway. Thus, Cph2 is an integral part of the regulatory circuit for GI colonization that regulates glycolytic flux. RNA-seq shows a significant overlap in genes differentially regulated by Cph2 and hypoxia, and Cph2 is important for optimal expression of some hypoxia-responsive genes in glycolysis and the citric acid cycle. We suggest that Cph2 and Upc2 regulate hypoxia-responsive expression in different pathways, consistent with a synthetic lethal defect of the cph2 upc2 double mutant in hypoxia.
2015-08-05 | GSE71728 | GEO
Project description:The sterol-regulatory element binding protein (SREBP) transcription factors are central transcriptional regulators of sterol- and fatty acid metabolism. Using a suite of human haploid genetic screens, we identify the SREBP Regulating Gene (SPRING; C12ORF49) as a novel regulator of this pathway. SPRING is a glycosylated Golgi-resident membrane protein. Genetic ablation of SPRING in human Hap1 cells, murine Hepa1-6 hepatoma cells, and in primary murine hepatocytes leads to a marked reduction in SREBP signaling. In mice, deletion of Spring results in embryonic lethality. However, we show that adenoviral-mediated silencing of hepatic Spring expression also attenuates the SREBP response. Mechanistically, we demonstrate that attenuated SREBP signaling in SPRINGKO cells is a result of reduced SREBP cleavage-activating protein (SCAP) and its mislocalization. Whereas in control cells SCAP cycles between the ER and the Golgi in a sterol-dependent manner, in SPRINGKO cells SCAP is trapped in the Golgi irrespective of the cellular sterol status. Consistent with limited functional SCAP in SPRINGKO cells, reintroducing SCAP restores SREBP-dependent signaling, cholesterol biosynthesis, and lipoprotein uptake. Consistent with SREBP signaling being required for cell growth and proliferation, a wide range of human tumor cell lines display dependency on SPRING expression. In conclusion, we identify SPRING as a previously unrecognized determinant of the SREBP pathway that is essential for proper SCAP function.
2020-01-23 | GSE143530 | GEO
Project description:Vitamin D3 metabolites are capable of controlling gene expression in mammalian cells through two independent pathways: vitamin D receptor (VDR) and sterol regulatory element-binding protein (SREBP) pathways. In the present study, we dissect the complex biological activity of vitamin D by designing synthetic vitamin D3 analogs specific for VDR or SREBP pathway, i.e., a VDR activator that lacks SREBP inhibitory activity, or an SREBP inhibitor devoid of VDR activity.
2019-07-27 | GSE134965 | GEO
Project description:Sterol regulatory element binding proteins (SREBPs) are key transcriptional regulators of lipid metabolism. To define functional differences between the three mammalian SREBPs we are using genome-wide ChIP-seq with isoform-specific antibodies and chromatin from select tissues of mice challenged with different dietary conditions that enrich for specific SREBPs. We show hepatic SREBP-2 binds preferentially to two different gene-proximal motifs. Gene ontology analyses suggests SREBP-2 targets lipid metabolic processes as expected but apoptosis and autophagy gene categories were also enriched. We show SREBP-2 directly activates autophagy genes during cell sterol depletion, conditions known to induce both autophagy and nuclear SREBP-2 levels. Additionally, SREBP-2 knockdown during nutrient depletion decreased autophagosome formation and lipid droplet association of the autophagosome targeting protein LC3. Thus, the lipid droplet could be viewed as a third source of cellular cholesterol, which along with sterol synthesis and uptake, is also regulated by SREBP-2. Examination of hepatic SREBP-2 binding using ChIP-Seq. One ChIP-Seq dataset and one IgG control.
2011-03-22 | E-GEOD-28082 | biostudies-arrayexpress