Dissection of the promoter of the <i>HAP4</i> gene in <i>S. cerevisiae</i> unveils a complex regulatory framework of transcriptional regulation

Brons, Janynke F.; Jong, Marianne de; Valens, M.; Grivell, Leslie A.; Bolotin‐Fukuhara, Monique; Blom, Joke

doi:10.1002/yea.886

Cited by 22 publications

(16 citation statements)

References 18 publications

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“…We tested for Cat8 binding at the HAP4 and SIP4 promoters because of previous studies showing in vitro binding (6,25). SIP4 encodes a homolog of Cat8 that participates in the activation of some CAT8-dependent genes, and HAP4 encodes a transcription factor that activates genes expressed abundantly in aerobically grown cells (41).…”

Section: Resultsmentioning

confidence: 99%

“…This widely acting transcriptional repressor exits the nucleus when phosphorylated, relieving repression of dozens of genes, including CAT8 (13). Subsequent production of the Cat8 transcription factor and activation via Snf1-dependent phosphorylation (11,36) up-regulates gluconeogenic and glyoxylate cycle genes as well as several transcription factors, such as SIP4 and HAP4 (6,25).…”

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confidence: 99%

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Combined Global Localization Analysis and Transcriptome Data Identify Genes That Are Directly Coregulated by Adr1 and Cat8

Tachibana

Yoo

Tagne

et al. 2005

Molecular and Cellular Biology

144

164

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In Saccharomyces cerevisiae, glucose depletion causes a profound alteration in metabolism, mediated in part by global transcriptional changes. Many of the transcription factors that regulate these changes act combinatorially. We have analyzed combinatorial regulation by Adr1 and Cat8, two transcription factors that act during glucose depletion, by combining genome-wide expression and genome-wide binding data. We identified 32 genes that are directly activated by Adr1, 28 genes that are directly activated by Cat8, and 14 genes that are directly regulated by both. Our analysis also uncovered promoters that Adr1 binds but does not regulate and promoters that are indirectly regulated by Cat8, stressing the advantage of combining global expression and global localization analysis to find directly regulated targets. At most of the coregulated promoters, the in vivo binding of one factor is independent of the other, but Adr1 is required for optimal Cat8 binding at two promoters with a poor match to the Cat8 binding consensus. In addition, Cat8 is required for Adr1 binding at promoters where Adr1 is not required for transcription. These data provide a comprehensive analysis of the direct, indirect, and combinatorial requirements for these two global transcription factors.Cells respond to stresses such as variations in temperature, pH or osmotic or nutrient conditions by altering the expression of genes that allow the cell to respond to the new environment (10). These transcriptional changes are initiated by signals that converge on a limited number of transcription factors, which then act combinatorially to control many genes in multiple pathways. Microarrays can be used to identify these coordinated, combinatorial responses by detecting both the localization of key transcription factors and the corresponding changes in the transcriptome (1).

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Combined Global Localization Analysis and Transcriptome Data Identify Genes That Are Directly Coregulated by Adr1 and Cat8

Tachibana

Yoo

Tagne

et al. 2005

Molecular and Cellular Biology

144

164

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“…Finally, the HAP elements are also involved in regulation of HXT5 expression. Activity of the Hap2/3/4/5p complex, which probably binds to the HAP elements in the HXT5 promoter, is dependent on the Hap4p subunit, whose transcription is repressed by glucose (Brons et al, 2002;DeRisi et al, 1997;Forsburg and Guarente, 1989). Thus, the HAP elements may also contribute to HXT5 expression specifically when glucose is absent, i.e.…”

Section: Discussionmentioning

confidence: 99%

HXT5 expression is under control of STRE and HAP elements in the HXT5 promoter

Verwaal

Arako

Kapur

et al. 2004

Yeast

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Hexose transporter (Hxt) proteins transport glucose across the plasma membrane in the yeast Saccharomyces cerevisiae. Recently, we have shown that expression of HXT5 is regulated by the growth rate of the cells. Because gene expression is regulated by binding of specific transcription factors to regulatory elements in the promoters of genes, the presence of putative regulatory elements in the promoter of HXT5 was determined by computer-assisted analysis. This revealed the presence of two putative stress-responsive elements (STREs), one putative post-diauxic shift (PDS) element and two putative Hap2/3/4/5p (HAP) complex binding elements. The involvement of these elements was studied by using mutations in a HXT5 promoter-LacZ fusion construct. Growth during various conditions that result in low growth rates of yeast cells revealed that the STRE most proximal to the translation initiation site seemed to be involved in particular in regulation of HXT5 expression during growth at decreased growth rates. In addition, the HAP elements seemed to be required during growth on non-fermentable carbon sources. The PDS element and, to a lesser extent, the other STRE showed particular involvement in regulation of HXT5 expression during growth on ethanol. Finally, it was shown that the PKA pathway, which is known to be involved in expression of STRE-regulated genes, was also involved in regulation of HXT5 expression. A possible mechanism by which expression of HXT5 could be regulated by the transcriptional regulatory elements in the promoter is discussed.

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“…Tai et al (11) report that HAP4 mRNA is present in carbon-limited cultivations even under anaerobic conditions where Hap4 has no obvious role. The promoter of HAP4 has three carbon source responsive elements (12), which require a functional Cat8 for the activation (a transcription factor that activates gluconeogenic genes); however, deletion of CAT8 had no effect on the steady state level of HAP4 expression (13). It has not been proven in vivo that Mig1 binds to the HAP4 promoter even though it is generally accepted that HAP4 expression is under glucose repression via Mig1.…”

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confidence: 99%

Hap4 Is Not Essential for Activation of Respiration at Low Specific Growth Rates in Saccharomyces cerevisiae

Raghevendran

Patil

Olsson

et al. 2006

Journal of Biological Chemistry

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In Saccharomyces cerevisiae, the heme-activated protein complex Hap2/3/4/5 plays a major role in the transcription of genes involved in respiration. Thus, overexpression of HAP4 has been shown to result in a 10% increase in the respiratory capacity. Here the physiology of a HAP4-deleted S. cerevisiae strain was investigated, and we found that the hap4⌬ S. cerevisiae exhibited poor growth on ethanol, although the growth rate on glucose was indifferent from the wild type in aerobic as well as anaerobic cultures. Moreover, it exhibited a large (75%) reduction in the critical glucose uptake rate at which fermentative metabolism is onset, indicating a substantial reduction in respiratory capacity. We also performed whole genome transcription analysis for the hap4⌬ and the wild type, grown in carbonlimited chemostat cultures operated at a dilution rate of 0.05 h ؊1 .Although both strains exhibited respiratory metabolism, there was significant change in expression of many genes in the hap4⌬ strain. These genes are involved in several different parts of the metabolism, including oxidative stress response, peroxisomal functions, and energy generation. This study strongly indicates that Hap4 activation only occurs at intermediate specific growth rates, below which the transcription of genes responsible for respiration is dependent on the Hap2/3/5 complex and above which the Hap4 protein augments the transcription. Furthermore, statistical analysis of the transcription data and integration of the data with a genome scale metabolic network provided new insight and evidence for the role of Hap4 in transcriptional regulation of mitochondrial respiration.Respiration plays a central role in providing Gibbs free energy required for growth and overall cellular function. The respiratory chain is closely coupled with the operation of the tricarboxylic acid cycle as it ensures oxidation of NADH generated in this cycle. Proper functioning of respiration is therefore essential not only for providing Gibbs free energy but also for operation of the tricarboxylic acid cycle. Consequently, many metabolic diseases result either directly or indirectly from altered functioning of respiration. Moreover, respiration and energy metabolism are of particular interest in metabolic engineering, where the objective may be to design new cell factories for production of chemicals that demand energy for their synthesis. The yeast Saccharomyces cerevisiae is not only an important cell factory for production of fuels, chemicals, and pharmaceuticals but also serves as an important eukaryotic model organism for studying human diseases, thus making it an attractive model for studying respiration.In S. cerevisiae, the heme-activated protein complex Hap2/3/4/5 plays a major role in orchestrating the transcription of genes involved in the tricarboxylic acid cycle, the electron transport chain, ATP generation, and mitochondrial biogenesis by binding to the CCAAT box at the upstream activation sequence of genes encoding enzymes of these pathways (1). Binding is ...

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Dissection of the promoter of the HAP4 gene in S. cerevisiae unveils a complex regulatory framework of transcriptional regulation

Cited by 22 publications

References 18 publications

Combined Global Localization Analysis and Transcriptome Data Identify Genes That Are Directly Coregulated by Adr1 and Cat8

Combined Global Localization Analysis and Transcriptome Data Identify Genes That Are Directly Coregulated by Adr1 and Cat8

HXT5 expression is under control of STRE and HAP elements in the HXT5 promoter

Hap4 Is Not Essential for Activation of Respiration at Low Specific Growth Rates in Saccharomyces cerevisiae

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