SEARCH Journal home Current Issue editorial science & society reviews scientific reports Advance Online Publication Archive Press releases Aims and scope Authors and referees Guide for authors Guide for referees Contact editors Advisors & Advisory Editorial Board Submit a Manuscript Customer Services Subscriptions Order sample copy Purchase articles Reprints and permissions Contact NPG Advertising www.embo.org EMBO reports 7, 5, 496 â € “499 (2006) doi:10.1038/sj.embor.7400679 Yeast Gal4: a transcriptional paradigm revisited Ana Traven1, Branka Jelicic2 & Mary Sopta2 1 St Vincent's Institute, 9 Princes Street, Fitzroy, Vic 3065, Australia 2 Department of Molecular Biology, Rudjer Boskovic Institute, Bijenicka 54, Zagreb, Croatia To whom correspondence should be addressed Mary Sopta Tel:+38 5 1456 0948; Fax: +38 5 1456 1177; msopta@irb.hr Received 21 November 2005; Accepted 6 February 2006. Abstract During the past two decades, the yeast Gal4 protein has been used as a model for studying transcriptional activation in eukaryotes. Many of the properties of transcriptional regulation first demonstrated for Gal4 have since been shown to be reiterated in the function of several other eukaryotic transcriptional regulators. Technological advances based on the transcriptional properties of this factor â € ”such as the two-hybrid technology and Gal4-inducible systems for controlled gene expression â € ”have had far-reaching influences in fields beyond transcription. In this review, we provide an updated account of Gal4 function, including data from new technologies that have been recently applied to the study of the GAL network. EMBO reports 7, 5, 496 â € “499 (2006) doi:10.1038/sj.embor.7400679 Introduction Transcriptional regulation of protein-coding genes in eukaryotes requires the combined action of many proteins impinging on the promoter region of a gene. In addition to RNA polymerase II, these proteins fall into the broad classes of activator or repressor proteins â € ”coactivator or corepressor complexes â € ”and general transcription factors. Several of these proteins are conserved between yeast and mammals, thus studies in the yeast Saccharomyces cerevisiae have been particularly useful for the study of gene transcription by RNA polymerase II. One of the earliest model systems for studying transcriptional regulation was that of the galactose-mediated induction of gene expression in yeast, which is under the control of the transcriptional activator Gal4. Pioneering studies on Gal4 from the Ptashne laboratory shaped our conceptual understanding of transcriptional activation in eukaryotes (reviewed in Ptashne & Gann, 2002). These studies showed the modular nature of the DNA-binding and activation domains of transcriptional activators and, as Gal4 could activate transcription when expressed in mammalian cells, that the activation mechanism is conserved in eukaryotes. Ultimately, they showed that the function of the activator is to recruit the transcriptional machinery to the promoter, as fusions of the Gal4 DNA-binding domain to targets in the transcriptional machinery could function as activators in their own right. The GAL regulon The GAL genes are required for the growth of yeast on galactose and they comprise structural (GAL1, GAL10, GAL2 and GAL7) and regulatory (GAL4, GAL80 and GAL3) genes. The products of the GAL genes are required for the transport of galactose into the cell and its metabolism through the glycolytic pathway. Induction of the GAL structural genes by galactose is dependent on the transcriptional activator Gal4 that operates through an upstream activating sequence (UASGAL) present in their promoters. The number of UASGAL sites and their relative affinity for Gal4 vary among the GAL genes and this leads to differential activation (Lohr et al, 1995). The UASGAL is sufficient for mediating galactose induction through Gal4 when fused to a heterologous gene, and this property has been widely applied to the generation of inducible heterologous gene expression systems. A genome-wide analysis of promoters bound by Gal4 and induced by galactose found that in addition to the previously identified GAL genes, MTH1, PCL10 and FUR4 also belong to the GAL regulon (Ren et al, 2000). These genes are not required for galactose metabolism, but rather for global adaptation to growth on galactose. For example, the induction of MTH1, a repressor of glucose transporter gene expression, results in the inhibition of glucose transport when glucose is depleted. Approximately 300 potential Gal4-binding sites have been identified throughout the yeast genome. Apart from promoter regions, sites can be found in open reading frames (ORFs), and such sites in the acetyl-CoA carboxylase 1 gene (ACC1) can bind Gal4 and lead to decreased ACC1 expression in the presence of galactose (Li & Johnston, 2001). However, Gal4 sites in the ACC1 ORF are not conserved in yeast species and their elimination has no consequence for growth on galactose. It has been proposed that they are 'noise' in the occurrence of Gal4-binding sites in the genome (Li & Johnston, 2001). What determinants influence the binding or non-binding of Gal4 to the various binding sites in the genome is not yet clear. Chromatin structure might regulate the accessibility of Gal4 to some potential sites. In the case of GAL1 â € “GAL10, GAL7 and GAL80 promoters, the UAS element is found in a nucleosome-free position regardless of the carbon source (Lohr, 1997). By contrast, nucleosomes are positioned over the TATA boxes and initiation sites and these are disrupted after galactose induction in a Gal4-dependent manner (Lohr, 1997). Other mechanisms that could influence the occupancy of the UASGAL by Gal4 include the binding affinities of the individual sites, their number and the vicinity of other regulatory regions. The Gal4 â € “Gal80 regulatory axis Gal4 is an 881-amino-acid protein with a Zn â € “Cys binuclear cluster-type DNA-binding domain, a linker domain, a dimerization domain and two acidic activation domains (ARI and ARII; Lohr et al, 1995). The first gal- mutants to be isolated contained mutations in residues throughout the molecule, but with significant clustering in the DNA-binding domain (Johnston & Dover, 1987). The consensus Gal4-binding site is a 17mer of sequence 5'-CGG-N11-CCG-3'. The crystal structure of the minimal DNA-binding domain (amino acids 1 â € “65) in complex with a consensus UAS shows that Gal4 binds as a dimer (Marmorstein et al, 1992). The Gal4 Zn â € “Cys domains contact the CGG elements directly, whereas the linker and dimerization domains interact with the phosphate backbone of the spacer residues in the 17mer. The CGG residues and the exact length of the spacer region are crucial to Gal4 binding (Liang et al, 1996). Domain-swap experiments with activators of the same family (Gal4, Put3 and Ppr1) showed that DNA-binding specificity is a function of a 19-amino-acid region C-terminal to the Zn â € “Cys cluster and not of the Zn â € “Cys cluster itself (Reece & Ptashne, 1993). Gal4 binding to multiple UASGAL elements is cooperative in vitro and leads to synergistic activation of transcription in vivo (Kang et al, 1993; Giniger & Ptashne, 1988). Gal4 has some ability to bind non-Gal4 UAS elements in vivo as shown by the activation of the proline utilization (PUT) pathway genes in a galactose-dependent manner in a put3 background (D'Alessio & Brandriss, 2000). In the absence of galactose, Gal4 is inactive owing to the binding of the repressor Gal80 to the Gal4-activation domain, which indicates that the interaction of this domain with the transcription machinery is prevented (Fig 1). For example, it has been shown that binding of Gal80 to Gal4 inhibits subsequent binding of the TATA-binding protein (TBP) or TFIIB in vitro (Wu et al, 1996) and that Gal80 blocks interactions of the Gal4-activation domain with Spt â € “Ada â € “Gcn5 acetyltransferase (SAGA) and NuA4 complexes (Carrozza et al, 2002). Relief of inhibition by Gal80 is dependent on a functional Gal3 protein. Biochemical studies have shown that Gal3 interacts with Gal80, and it is this interaction that is sensitive to the presence of galactose (Zenke et al, 1996). How exactly Gal3 â € “Gal80 complex formation relieves Gal80 inhibition of Gal4 is not yet known. It was long believed that Gal3 interacts with Gal80 in the nucleus to elicit a conformational change in the Gal80 â € “Gal4 complex (Leuther & Johnston, 1992). In favour of this model, recent studies using fluorescence resonance energy transfer (FRET) microscopy have confirmed that Gal4 and Gal80 stay associated in the presence of galactose (Bhaumik et al, 2004). However, localization studies show that Gal3 is exclusively a cytoplasmic factor. They also indicate that Gal80 dissociates from Gal4 on binding to Gal3 and 'shuttles' between the cytoplasm and the nucleus (Peng & Hopper, 2000). Artificial tethering of Gal3 in the cytoplasm does not preclude galactose-dependent activation of Gal4, and chromatin immunoprecipitation (ChIP) studies have shown that the association of Gal80 with the UASGAL is diminished when GAL gene expression is activated (Peng & Hopper, 2002). Figure 1 Transcriptional activation by Gal4. Under non-inducing conditions, Gal4 activity is blocked by the interaction of Gal80 with the Gal4-activation domain. Gal4 levels are regulated by the F-box protein Grr1. On galactose induction, Gal80 is removed from the Gal4-activation domain, which is then able to recruit the transcriptional machinery. Dsg1 regulates turnover of transcriptionally active Gal4. GTFs, general transcription factors; SAGA, Spt-Ada-Gcn5 acetyltransferase; TBP, TATA-binding protein. Transcriptional activation by recruitment Gal4 activates transcription by recruiting coactivators and the general transcription machinery to promoter regions through its activation domain (Fig 1). Important questions remain as to what are the functional targets of Gal4 and whether it contacts one or many proteins during the process of recruitment. Proteins that have been shown to interact specifically with the Gal4-activation domain include TBP (Melcher & Johnston, 1995; Wu et al, 1996), TFIIB (Wu et al, 1996), Gal11 (a component of Mediator; Jeong et al, 2001), Cdk8 (also known as Srb10; Ansari et al, 2002), SWI/SNF (Yudkovsky et al, 1999), SAGA (Brown et al, 2001; Bhaumik et al, 2004), Srb4 (another component of Mediator; Koh et al, 1998) and proteasome components Sug1 (Gonzalez et al, 2002) and Sug2 (Chang et al, 2001). The recent application of ChIP analyses and FRET microscopy to address the issues of factor occupancy and the kinetics of factor recruitment to the GAL genes have started to define the in vivo functions of the Gal4-activation domain. The conclusion of these studies is that SAGA is a physiologically relevant and direct target of Gal4. SAGA recruitment is dependent on the activation domain of Gal4 and on Spt20, which is a SAGA component essential to the integrity of the complex (Bhaumik & Green, 2001; Bryant & Ptashne, 2003; Larschan & Winston, 2001). Recruitment of SAGA to the UASGAL does not require additional factors other than Gal4, which suggests that it is a direct target of the Gal4-activation domain (Bhaumik et al, 2004; Larschan & Winston, 2001, 2005; Bryant & Ptashne, 2003). The histone acetyl transferase (HAT) component of SAGA, Gcn5, is not required for SAGA recruitment and pre-initiation complex (PIC) formation (Bhaumik & Green, 2001), therefore SAGA works as a scaffold that helps to assemble the PIC at the promoter, and not as a HAT. In the absence of Spt3 â € ”another SAGA subunit â € ”SAGA recruitment is modestly reduced, whereas PIC formation and transcription are significantly reduced (Bhaumik & Green, 2001; Larschan & Winston, 2001). This is most probably owing to the requirement of Spt3 for recruitment of TBP to the promoter of GAL genes (Larschan & Winston, 2001). As reported by Bhaumik and colleagues, FRET microscopy has revealed that the Tra1 subunit in the SAGA complex is the target of the Gal4-activation domain (Bhaumik et al, 2004). The Gal4 â € “Tra1 interaction depends on the presence of both the activation and DNA-binding domains of Gal4, which indicates that Gal4 has to be bound to the UASGAL to interact with SAGA (Bhaumik et al, 2004). ChIP studies have shown that SAGA is the first complex to bind the GAL gene promoters on induction (Bryant & Ptashne, 2003; Bhaumik & Green, 2001), which supports the evidence that it is a direct target of Gal4. Is SAGA the only direct target of the Gal4 activation domain, or can Gal4 target multiple coactivators during transcriptional activation? Recruitment of Mediator subunits to the UASGAL has been shown (Kuras et al, 2003; Bhaumik et al, 2004; Bryant & Ptashne, 2003; Lemieux & Gaudreau, 2004; Larschan & Winston, 2005). However, reports vary as to whether or not SAGA is required for Mediator recruitment. Green and co-workers have shown that SAGA is essential for Mediator recruitment to the UASGAL, and they were unable to detect an interaction between the Srb4 and Gal11 subunits of Mediator and Gal4 by FRET microscopy (Bhaumik et al, 2004). Conversely, three reports have shown that Mediator can be recruited to GAL genes independently of SAGA (Bryant & Ptashne, 2003; Larschan & Winston, 2005; Lemieux & Gaudreau, 2004). Results of recent in vitro cross-linking studies support the idea that Mediator might be bound directly by Gal4, as they have shown that both SAGA and Mediator interact directly with Gal4 and the unrelated acidic activator Gcn4 (Reeves & Hahn, 2005; Fishburn et al, 2005). However, some reports show that the recruitment of Mediator to the Gal4-dependent genes in vivo is diminished in the absence of SAGA (Larschan & Winston, 2005) or modestly delayed (Lemieux & Gaudreau, 2004), whereas others report that Mediator binds with similar kinetics in the absence of SAGA, but that this does not lead to productive PIC formation (Bryant & Ptashne, 2003). In conclusion, we believe that the data so far suggest that Mediator is probably a direct target of the activation domain of Gal4, but that the presence of SAGA at the UASGAL stabilizes the interactions of the Mediator subunits and is required for formation of the PIC and gene transcription. It is possible that the Gal4-activation domain interacts directly with other transcription factors in vivo; however, such interactions, if they exist, must be weak and need to be stabilized by many contacts with several proteins or by a post-translational modification of Gal4, such as phosphorylation. The general transcription factors TBP and TFIIB bind to the Gal4-activation domain in vitro (Wu et al, 1996), but FRET microscopy failed to identify an in vivo interaction between these transcription factors and Gal4 in the presence of galactose (Bhaumik et al, 2004). Furthermore, recruitment of TBP to Gal4-dependent promoters requires factors such as Spt3, Ada1, Spt7 and Spt20 (all SAGA subunits, Srb9 and Srb10 (Srb8 â € “Srb11 complex/Mediator), in addition to Gal4 (Dudley et al, 1999; Bhaumik & Green, 2001, 2002; Larschan & Winston, 2001, 2005). In the case of the Srb8 â € “Srb11 complex, SAGA is required for binding of Srb9 to the UASGAL (Larschan & Winston, 2005). Similarly, ChIP studies suggest that Mediator, TAFs and RNA polymerase II are required for efficient recruitment of SWI/SNF to the GAL1 promoter (Lemieux & Gaudreau, 2004). Gal4 regulation by post-translational modification Gal4 undergoes a series of phosphorylations, which produces three distinct migratory forms (a, b and c). Forms b and c are produced by the phosphorylation of form a. Form c is the slowest migrating of the three and is specific to Gal4, which is transcriptionally active in the presence of galactose, whereas form b exists even under non-inducing conditions (Sadowski et al, 1991; Muratani et al, 2005). Phosphorylation sites have been defined at Ser 691, Ser 696, Ser 699, and Ser 837 (Hirst et al, 1999; Sadowski et al, 1996). Form c corresponds to Gal4 phosphorylated at Ser 699 and Ser 837, whereas form b seems to contain only phospho-Ser 837 Gal4 (Sadowski et al, 1991; Muratani et al, 2005). The DNA-binding domain is also phosphorylated (Sadowski et al, 1996), but the exact residues have not been mapped. Phosphorylation of Gal4 occurs when the activator is engaged in activating transcription. It is executed by the RNA polymerase II-associated kinases Kin28(TFIIH) and Cdk8(Srb10) (Hirst et al, 1999) and requires other proteins in addition to Gal4, such as Mediator and SAGA subunits, general transcription factors and elongation factors (Muratani et al, 2005). The two kinases show different specificities in vitro: Kin28 predominantly phosphorylates Ser 837, whereas Srb10 phosphorylates Ser 699 (Hirst et al, 1999). How crucial is phosphorylation for Gal4 activity? The data so far suggest that phosphorylation regulates Gal4, but it is not absolutely essential for its activity. As shown by Ser to Ala mutagenesis, phosphorylation of residues other than Ser 699 seems to be irrelevant for activation of GAL genes (Rohde et al, 2000). Even phospho-Ser699 becomes dispensable when the concentration of galactose in the cell is high (Rohde et al, 2000), suggesting that this is a fine-tuning, rather than an on â € “off, mechanism. Furthermore, some mutations that severely impair the formation of Gal4 form c in galactose media, such as spt3 and bdf1, have only a modest effect on transcriptional activation by Gal4 (Muratani et al, 2005). The functional consequences of Gal4 phosphorylation are not fully understood, but some possibilities are emerging. Ser to Ala mutation at residue 699 affects induction of GAL gene transcription only when cells are GAL80+ (Sadowski et al, 1996), suggesting that phospho-Ser 699 could have a role in stabilizing a Gal80 â € “Gal4 conformation that is permissive to transcriptional activation. Another possible role for phospho-Ser 699 (and possibly phospho-Ser 837) could be to mark the Gal4 proteins that have already recruited the PIC to promoters, which would then target them for proteolysis with important consequences for productive versus unproductive expression of GAL genes (see below, Muratani et al, 2005). Tansey and colleagues have recently uncovered a role for the ubiquitin degradation system in the turnover and activity of Gal4 (Muratani et al, 2005). Two systems operate in the regulation of Gal4 stability in vivo, through two separate F-box proteins Grr1 and Dsg1. Grr1 restricts the activity of Gal4 under non-inducing conditions (Fig 1) by degrading forms a and b of Gal4. Conversely, the Dsg1-dependent mechanism acts positively on the expression of GAL genes by turning over the transcriptionally active Gal4c (Fig 1). ChIP analyses have shown that Dsg1 is recruited to the UASGAL under inducing conditions. The role of Dsg1 is tied to the appropriate phosphorylation of the C-terminal domain of RNA polymerase II and the generation of translationally productive mRNA species. It is possible that phosphorylation of Gal4 could create a binding surface for Dsg1, which would in turn lead to ubiquitin-dependent proteolysis of Gal4c. The transition from initiation to elongation and subsequent post-transcriptional events that produce translationally competent mRNAs (Muratani et al, 2005) are thus enabled. Phosphorylation, however, is probably not the only way by which Gal4c is recognized by Dsg1. In contrast to the deletion of DSG1, which completely abrogates Gal4 activity, the absence of Gal4c only modestly reduces Gal4-dependent transcription (Muratani et al, 2005). Furthermore, Dsg1 might have other targets in the transcription machinery that need to be degraded for Gal4-dependent transcription to be productive. Conclusions Transcriptional regulation of protein-encoding genes is a complex biochemical process that has yet to be fully explained. Studies on the Gal4-regulatory paradigm have greatly enhanced our understanding of transcriptional regulation in S. cerevisiae and have provided a conceptual framework for studies of transcriptional control in other organisms. 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Science 272: 1662 â € “1665 | PubMed | ISI | ChemPort | Top of page MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated RESEARCH Targeting of Swi/Snf to the yeast GAL1 UAS G requires the Mediator, TAF II s, and RNA polymerase II The EMBO Journal Article (13 Oct 2004) Yeast homolog of a cancer-testis antigen defines a new transcription complex The EMBO Journal Article (09 Aug 2006) Regions of GAL4 critical for binding to a promoter in vivo revealed by a visual DNA-binding analysis The EMBO Journal Article (01 May 2003) Regions of GAL4 critical for binding to a promoter in vivo revealed by a visual DNA-binding analysis The EMBO Journal Article (01 May 2003) See all 27 matches for Research top This article Email link to a friend Download PDF Rights and permissions Reprints More articles like this Abstract Acknowledgements References Figures & tables Next article Previous article Privacy PolicyCopyright  © 2006 by the European Molecular Biology Organization