Transcriptional regulation of the squalene synthase gene (ERG9) in the yeast Saccharomyces cerevisiae

Kennedy, Matthew A.; Barbuch, Robert J.; Bard, Martin

doi:10.1016/s0167-4781(99)00035-4

Cited by 75 publications

(75 citation statements)

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“…The S288c background has several mutations in regulators of respiration and carbon metabolism, including Hap1p and Mig3p (Gaisne et al 1999;Lewis and Gasch 2012); however several of the hotspots we observe are cross specific, indicating that natural variation in carbon responses in wild strains also contributes to differences in ethanol tolerance (Lewis et al 2010). Hap1p also controls genes involved in ergosterol biosynthesis, which affects membrane fluidity and thus ethanol tolerance (Kennedy et al 1999;Jensen-Pergakes et al 2001;Tamura et al 2004). Likewise, variation in fatty acid consumption, controlled in part by the Oaf1 transcription factor, can alter the membrane content of cells to directly affect ethanol resistance (Chi and Arneborg 1999;You et al 2003;Lockshon et al 2007).…”

Section: Discussionmentioning

confidence: 85%

“…None of the pairs of hotspots with overlapping target sets shown in Figure 4 were identified as epi-hotspots, indicating that most of the overlap we initially observed represents additive hotspot effects. However, we uncovered several other epi-hotspots involving two or more regions implicated from the 1D mapping regimes: for example the interaction between peak 13 (Hap1p) and peak 1 (Oaf1p) represents an epi-hotspot-the candidate regulators encoded at these loci both affect membrane fluidity through ergosterol (Kennedy et al 1999;Jensen-Pergakes et al 2001;Tamura et al 2004) and fatty acid composition (Karpichev et al 1997;Karpichev et al 2008), respectively. Several loci were associated with multiple epi-hotspots, including peak 13 (HAP1) linked to four epi-hotspots, and peak 4 (MAT-ALPHA1), peak 7 (URA3), peak 12, peak 17 (MKT1), and peak 31 (FAA2) that were each linked to three epi-hotspots.…”

Section: Interactions Between Hotspots Indicate Additive and Epistatimentioning

confidence: 99%

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Genetic Architecture of Ethanol-Responsive Transcriptome Variation in Saccharomyces cerevisiae Strains

et al. 2014

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Natural variation in gene expression is pervasive within and between species, and it likely explains a significant fraction of phenotypic variation between individuals. Phenotypic variation in acute systemic responses can also be leveraged to reveal physiological differences in how individuals perceive and respond to environmental perturbations. We previously found extensive variation in the transcriptomic response to acute ethanol exposure in two wild isolates and a common laboratory strain of Saccharomyces cerevisiae. Many expression differences persisted across several modules of coregulated genes, implicating trans-acting systemic differences in ethanol sensing and/or response. Here, we conducted expression QTL mapping of the ethanol response in two strain crosses to identify the genetic basis for these differences. To understand systemic differences, we focused on "hotspot" loci that affect many transcripts in trans. Candidate causal regulators contained within hotspots implicate upstream regulators as well as downstream effectors of the ethanol response. Overlap in hotspot targets revealed additive genetic effects of trans-acting loci as well as "epihotspots," in which epistatic interactions between two loci affected the same suites of downstream targets. One epi-hotspot implicated interactions between Mkt1p and proteins linked to translational regulation, prompting us to show that Mkt1p localizes to P bodies upon ethanol stress in a strain-specific manner. Our results provide a glimpse into the genetic architecture underlying natural variation in a stress response and present new details on how yeast respond to ethanol stress. N ATURAL variation in gene expression is hypothesized to be a major source of phenotypic variation between individuals (King and Wilson 1975;Oleksiak et al. 2002). Gene expression variation underlies differences in susceptibility to infectious disease (Li et al. 2010;Barreiro et al. 2012), drug sensitivity (Fay et al. 2004;Kvitek et al. 2008;Maranville et al. 2011;Hodgins-Davis et al. 2012;Chang et al. 2013), inflammation (Gargalovic et al. 2006Orozco et al. 2012), cardiovascular disease (Romanoski et al. 2010), metabolism (Fraser et al. 2010Rossouw et al. 2012;Skelly et al. 2013), morphology (Yvert et al. 2003Chin et al. 2012;Skelly et al. 2013), and even behavior (Ziebarth et al. 2012). Still, identifying the genetic and molecular mechanisms that underlie the expression variation is a major challenge.Expression quantitative trait loci (eQTL) mapping (reviewed in Gilad et al. 2008) is a powerful approach to dissect the genetic basis of expression differences. Transcript abundance is treated as a quantitative trait whose genetic determinants can be implicated by well-established linkage mapping techniques. The first eQTL studies in yeast illuminated the genetic landscape of gene expression-variation determinants under standard growth conditions (Brem et al. 2002;Yvert et al. 2003). Subsequent eQTL studies surveyed the genetic control of transcript abundance in Arabidopsi...

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Section: Discussionmentioning

confidence: 85%

Section: Interactions Between Hotspots Indicate Additive and Epistatimentioning

confidence: 99%

Genetic Architecture of Ethanol-Responsive Transcriptome Variation in Saccharomyces cerevisiae Strains

et al. 2014

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“…Like HMG2 (the anaerobic counterpart of the two hydroxymethylglutaryl-CoA reductase isoforms involved in mevalonate synthesis), ERG9 is positively regulated by fatty acids and is negatively regulated by oxygen, haem and sterols. 97,105 However, ERG9 activity remains quite high in cells grown anaerobically with ergosterol and oleate in excess. …”

Section: Oxygen-independent Isoprenoid and Squalene Synthesismentioning

confidence: 99%

Role of the non‐respiratory pathways in the utilization of molecular oxygen by Saccharomyces cerevisiae

Rosenfeld

Beauvoit

2003

Yeast

133

110

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Saccharomyces cerevisiae is a facultative anaerobe devoid of mitochondrial alternative oxidase. In this yeast, the structure and biogenesis of the respiratory chain, on the one hand, and the functional interactions of oxidative phosphorylation with the cellular energetic metabolism, on the other, are well documented. However, to our knowledge, the molecular aspects and the physiological roles of the non-respiratory pathways that utilize molecular oxygen have not yet been reviewed. In this paper, we review the various non-respiratory pathways in a global context of utilization of molecular oxygen in S. cerevisiae. The roles of these pathways are examined as a function of environmental conditions, using either physiological, biochemical or molecular data. Special attention is paid to the characterization of the so-called 'cyanide-resistant respiration' that is induced by respiratory deficiency, catabolic repression and oxygen limitation during growth. Finally, several aspects of oxygen sensing are discussed.

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“…Regulation of ergosterol in Saccharomyces cerevisiae has both intrinsic and practical interest as this pathway contains the targets of most antifungal drugs. Genes encoding enzymes of ergosterol biosynthesis are transcriptionally regulated in response to the need for ergosterol (Arthington-Skaggs et al 1996;DimsterDenk and Rine 1996;Smith et al 1996;Kennedy et al 1999) but in ways that differ markedly from the regulation of the corresponding genes in mammals (Dimster-Denk and Rine 1996; Davies et al 2005).…”

mentioning

confidence: 99%

“…A HAP1 mutant allele can cause lower expression in several ergosterol biosynthetic genes with a corresponding reduction in ergosterol levels (Tamura et al 2004). Yer064Cp, a nuclear protein of unknown function, is important for the activation of some ERG genes (Kennedy et al 1999;Germann et al 2005). Finally, deletion of MOT3, a zincfinger protein that can act as both a transcriptional activator and a repressor, leads to increased expression of ERG2, ERG6, and ERG9 (Hongay et al 2002).…”

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confidence: 99%

A Role for Sterol Levels in Oxygen Sensing in Saccharomyces cerevisiae

Davies¹,

2006

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Upc2p and Ecm22p are a pair of transcription factors responsible for the basal and induced expression of genes encoding enzymes of ergosterol biosynthesis in yeast (ERG genes). Upc2p plays a second role as a regulator of hypoxically expressed genes. Both sterols and heme depend upon molecular oxygen for their synthesis, and thus the levels of both have the potential to act as indicators of the oxygen environment of cells. Hap1p is a heme-dependent transcription factor that both Upc2 and Ecm22p depend upon for basal level expression of ERG genes. However, induction of both ERG genes and the hypoxically expressed DAN/ TIR genes by Upc2p and Ecm22p occurred in response to sterol depletion rather than to heme depletion. Indeed, upon sterol depletion, Upc2p no longer required Hap1p to activate ERG genes. Mot3p, a broadly acting repressor/activator protein, was previously shown to repress ERG gene expression, but the mechanism was unclear. We established that Mot3p bound directly to Ecm22p and repressed Ecm22p-but not Upc2p-mediated gene induction.

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Transcriptional regulation of the squalene synthase gene (ERG9) in the yeast Saccharomyces cerevisiae

Cited by 75 publications

References 54 publications

Genetic Architecture of Ethanol-Responsive Transcriptome Variation in Saccharomyces cerevisiae Strains

Genetic Architecture of Ethanol-Responsive Transcriptome Variation in Saccharomyces cerevisiae Strains

Role of the non‐respiratory pathways in the utilization of molecular oxygen by Saccharomyces cerevisiae

A Role for Sterol Levels in Oxygen Sensing in Saccharomyces cerevisiae

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