Autophagic Punctum

point-of-view

Transcription 2:2, 71-77; March/April 2011; 2011 Landes Bioscience

Promoter architectures in the yeast ribosomal expression program

Maria Cristina Bosio,1 Rodolfo Negri2 and Giorgio Dieci1,*
1

Dipartimento di Biochimica e Biologia Molecolare; Universit degli Studi di Parma; Parma; 2Istituto Pasteur-Fondazione Cenci Bolognetti; Dipartimento di Biologia e Biotecnologie C. Darwin; Sapienza Universit di Roma; Rome, Italy

ibosome biogenesis begins with the -orchestrated expression of hundreds of genes, including the three large classes of ribosomal protein, ribosome biogenesis and snoRNA genes. Current knowledge about the corresponding promoters suggests the existence of novel class-specific transcriptional strategies and crosstalk between telomere length and cell growth control.

of the different classes of Pol II-served promoters involved in ribosome biogenesis (RP, ribi and snoRNA gene promoters), with the aim of providing a concise account of established knowledge. We will also briefly review some open questions about their architectures and the related biological implications. Cis-Regulatory Elements, Transcription Factors and Chromatin Architecture In spite of their common involvement in the task of building functional ribosomes, RP, ribi and snoRNA genes display, at the level of transcriptional promoters, distinctive features that will be detailed in this section. Ribosomal protein genes. In S. cerevisiae, the promoter regions of RP genes are known to be characterized by the presence of binding sites for the multifunctional DNA binding protein Rap1. Of the 138 S. cerevisiae RP gene promoters, 127 display predicted Rap1 binding sites2 and/ or have been found associated to Rap1 in vivo by chromatin immunoprecipitation (ChIP) analysis,3,4 8 have predicted Abf1 or Reb1 binding sites instead of Rap1 sites, while 3 appear unable to interact with any of these factors.3 The Rap1 binding sites occur in multiple copies, most frequently two, predominantly within a distance of 200500 bp from the transcription start site (TSS), with a marked preference for one specific orientation and for a head-to-tail organization of shortly spaced (515 bp) duplicated sites (Fig. 1).2,5 Rap1 binding to its target sites is constitutive, being maintained under repressive conditions.6-8 Other proteins have been shown

Key words: Ribosome biogenesis; snoRNA; ribosomal protein; Rap1; Tbf1; RNA polymerase II; telomeres. Submitted: 11/26/10 Revised: 12/15/10 Accepted: 12/16/10 DOI: 10.4161/trns.2.2.14486
*Correspondence to: Giorgio Dieci; Email: giorgio.dieci@unipr.it

At the heart of cell growth is ribosome biogenesis, one of the most complex, energyconsuming and tightly regulated processes in cells.1 At the transcriptional level, ribosome biogenesis has been best characterized in yeast, where it involves more than 750 individual transcription units and the coordinated activity of the three nuclear RNA polymerases (Pol I, Pol II and Pol III). In Saccharomyces cerevisiae, about 150 active copies of large rRNA and 5S rRNA genes are transcribed by Pol I and Pol III, respectively, while the 138 cytoplasmic ribosomal protein (RP) genes, the ~250 genes coding for other proteins involved in ribosome biogenesis (commonly referred to as ribi genes) and 76 of the 77 snoRNA genes are transcribed by Pol II, through a variety of promoters that ensure high levels of transcription and, at the same time, specific regulatory responses to external stimuli. Much has been learned recently about the combinations of cis-regulatory elements that compose such promoters, the DNA-binding proteins recognizing them, their general chromatin organization and the mechanisms of their activation and repression; yet, a number of fundamental issues still need to be clarified. Here, we will focus on the common and distinctive features

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Figure 1. Organization of typical RP, ribi and snoRNA gene promoters in Saccharomyces cerevisiae. The consensus sequences reported on the right (M, A or C; W, A or T; R, A or G; Y, C or T; K, G or T; N, any nucleotide) are based on the following references: Rap1,2 IFHL,6,16 Abf1,3,23,24 RRPE and PAC,20,21 Reb1,3,23 and Tbf1.23,24,29 The reported distances are with respect to the TSS (right-pointing arrow). Boxes with a thinner border indicate sequence elements occurring in a minority of promoters within each set. Poly(dA:dT) indicates either poly(dT) or poly(dA) stretches on the coding DNA strand, that prevail in RP and snoRNA promoters, respectively.

to specifically interact with and regulate, RP gene promoters in vivo: the forkhead DNA binding protein Fhl1, its genetic interactor Ihf1 and the zinc-finger transcription factor Sfp1.6,7,9,10 Curiously, however, none of these transcription factors (TFs) seems to recognize directly a specific site in RP gene promoters. Instead, both Fhl1 and Sfp1 are thought to bind indirectly, probably through interaction with Rap1,11,12 while Ihf1 recruitment occurs mostly through Fhl1.6,7,11 In agreement with the notion that Rap1 (and, in a few cases, Abf1) are the only TFs directly recognizing the upstream activating sequence (UAS) of RP genes, no other binding sites for known TFs have been identified at RP promoters. Instead, these regions are enriched for two sequence motifs that positively modulate transcription, but for which no specifically interacting TF has been unambiguously identified:

the poly(dA:dT)13 and IFHL6 elements. Poly(dA:dT) tracts are common in yeast promoters and favor transcription mostly by virtue of intrinsic structural properties that tend to disfavor nucleosome formation.13 Such sites are likely to greatly contribute to nucleosome depletion known to occur at RP promoter regions.14 The IFHL element appears to be necessary for RP promoter activity when present,6 through an unknown mechanism. Another motif, called RGE (rapid growth element, AAATTTT), is found in several RP gene promoters. Its usage could have contributed to the rewiring of mitochondrial and cytoplasmic RP transcriptional network during yeast evolution, but its role in RP gene transcription is unexplored.15,16 As a final remark, only six out of 138 RP gene promoters have a TATA box, in agreement with the general rule that stress-repressed housekeeping genes tend to be TATA-less

in S. cerevisiae.17 Relevant to this issue, a recent study has revealed the existence, in the promoter region of the RP gene RPS5, of multiple and functionally redundant AT-rich sequences that are required for transcription and recognized by TFIID.18 ribi genes. In addition to RP genes, ribosome biogenesis involves a large number (>230) of protein-coding genes, collectively defined as ribi regulon, that are co-regulated in response to environmental or genetic perturbations. Most (~150) ribi genes code for rRNA modification and ribosome assembly factors; others code for RNA polymerase I and III subunits, nucleotide metabolism enzymes, tRNA synthetases and translation and tRNA metabolism factors.10 The promoters of ribi genes are TATA-less and strongly enriched in two sequence motifs termed PAC and RRPE (Fig. 1).19-21 According to reference 10, PAC and RRPE are

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present in 47 and 55% of ribi promoters, respectively, with ~25% of them displaying both motifs. Remarkably, the motifs predominantly occur in the first 150 bp upstream from the start codon, which corresponds more to the position range of the TATA box than to the typical location of a yeast UAS. This has led to the suggestion that PAC and RRPE might act as alternative core promoter elements antagonizing TBP-dependent regulation.22 When the two motifs occur together, they tend to be spaced by less than 50 bp. The PAC is typically more proximal to the TSS than the RRPE, a configuration that might be required for regulatory purposes.19,21 Recent DNA-binding arrays and phage display screens identified Dot6/Pbf2 and Tod6/Pbf1 as PAC element binding factors,23-25 while Stb3 has been reported to recognize the RRPE sequence motif.24,26 There is increasing evidence that PAC sites function as Dot6/Tod6-dependent repressor elements under poor nutrient conditions or stress.24,27 Similarly, the RRPE appears to act as an Stb3dependent repressing sequence under the same conditions.25,28 Notably, the RRPE sequence includes two short poly(dA:dT) elements with opposing orientation, that are expected to disfavor nucleosome formation.14 The RRPE might thus be able to influence promoter activity both through interactions with regulatory proteins and by virtue of intrinsic structural properties. Further support for the role of Dot6/Tod6 and Stb3 as key players in ribi gene regulation arose from the recent identification of these proteins as targets of the TORC1-regulated protein kinase Sch9.25 Sfp1 is another known transcriptional regulator of ribi genes, and is also a TORC1-dependent phosphorylation target. Physical association of Sfp1 to ribi gene promoters, however, could not be demonstrated.25 snoRNA genes. Small nucleolar RNAs (snoRNAs) play a key role in rRNA biogenesis, yet their promoter architecture has remained almost totally unexplored since their discovery twenty years ago. As shown recently, the promoters of the majority of these genes are bound by the telomereassociated protein Tbf1 in S. cerevisiae.29 Tbf1 binds to a single ARCCCTAA sequence motif demarcating the upstream

border of the snoRNA promoter region. Tbf1 also binds to over 100 promoters of protein-coding genes (including several ribi genes) and to subtelomeric regions in the S. cerevisiae genome.29,30 As illustrated in Figure 1, snoRNA promoters display other distinctive features, in addition to the Tbf1 binding site. Unlike RP and ribi gene promoters, most of them contain a canonical TATA box. A poly(dA:dT) element is frequently present within 50 bp upstream of the TATA; an RRPE is found at a similar location in 15 promoters, sometimes in combination with a PAC element. Half of the Tbf1-associated promoters display, 2535 bp downstream of the Tbf1 site, a single binding site for Reb1, a versatile transcription factor that, like Tbf1, also associates to subtelomeric regions.29 Tbf1 appears to be required for full snoRNA gene expression, although significant levels of transcription remain after abolishing its binding. Reb1 and poly(dA:dT) also importantly contribute to promoter strength.29 There are intriguing parallels between the action of Tbf1 and Rap1 at snoRNA and RP gene promoters, respectively. The binding sites for both proteins demarcate the upstream border of the promoter region and positively modulate transcription in association with poly(dA:dT) elements; moreover, both proteins associate to different classes of promoters in the S. cerevisiae genome (RP, translation factor and glycolytic gene promoters for Rap1; 4 snoRNA and nonsnoRNA promoters for Tbf1), and they both appear to influence transcription through different mechanisms and interacting partners at the different classes of associated promoters.29,31 Nucleosomal organization. According to systems-level studies, two general types of nucleosomal architecture exist for yeast promoters. One type is characterized by a static architecture with characteristic nucleosome-depleted regions upstream of the TSS, in which TF binding sites are concentrated. Such promoters exhibit low transcriptional plasticity (quantifying the dynamic range of expression level) and tend to be TATA-less. The other type of promoters, highly enriched in TATA boxes, have higher nucleosome occupancy near the TSS, with TF binding sites overlapping nucleosome-associated regions

and high transcriptional plasticity.14,17,32 RP and ribi gene promoters basically belong to the first type. The promoters of snoRNA genes are similarly nucleosomedepleted;29 however, they display TATA boxes in most cases, thus arguing against any simple link between the presence of a TATA box and nucleosome profile at promoters. Remarkably, even though the Tbf1 binding site marks the upstream border of a nucleosome-free region (NFR) in snoRNA promoters, its inactivation does not affect the NFR. In contrast, Tbf1 substantially contributes to nucleosome exclusion at non-snoRNA promoters, where it selectively co-localizes with two interacting zinc-finger proteins, Vid22 and Ygr071c.29 Similarly to Tbf1, Rap1 has also been shown to affect nucleosome occupancy at only a subset of promoters,23 and its insulator activity is somewhat context-dependent.33 Moreover, Rap1 (and Abf1) binding sites seem more effective in depleting nucleosomes when accompanied by nearby sequence boundaries.14 These facts argue in favor of the existence of large sets of gene promoters whose nucleosome organization is mainly DNA-encoded.34 At the same time, they suggest that Rap1and Tbf1-dependent transcription activation may involve direct interaction with the transcription machinery, as the one recently demonstrated between Rap1 and the general transcription factor TFIID.35 This interaction appears strongly directional, involving a sophisticated tridimensional structure that would enhance the formation of transcriptional pre-initiation complexes on RP genes. This model, if further supported by in vivo observations, could contribute to explain why Rap1 in most cases acts exclusively on RP genes when present in head-to-head configuration with other genes. Open Issues As evident from the previous section, our knowledge about the composition, promoter organization and transcriptional regulation of the different regulons involved in yeast ribosome biogenesis has remarkably advanced in the last decade. However, several highly relevant questions have been left unanswered, or even newly opened, by this wealth of studies.

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Orphan DNA-binding proteins and cis-acting elements. The transcriptional regulation of RP and ribi genes involves at least two site-specific DNA-binding proteins, Fhl1 and Sfp1, whose binding sites are apparently missing in promoter regions, thus leaving open the question of their mode of recruitment. According to systematic studies of in vitro DNAbinding specificity of yeast TFs, Fhl1 recognizes a gACGCa consensus motif,23,24 while the zinc-finger protein Sfp1 can directly recognize the DNA motif aAAAWTTTt (W = A or T).24 The latter motif strongly resembles both the RRPE and the RP-associated RGE, thus suggesting the possibility that Sfp1 might directly interact with ribi promoters through the RRPE, and to RP genes through the RGE.16 We note that the binding specificities previously attributed to both Fhl1 and Sfp1 based on genome-wide ChIP data 3 overlap with the sequence motif bound by Rap1,2,23,24 thus simply reflecting the colocalization of these proteins with Rap1 at RP promoters. Another basic open issue concerns the nature of cis-elements and TFs that actually participate in ribi gene transcription. The ribi-associated PAC and RRPE motifs are closer to the TSS than typical yeast TF binding sites and negatively modulate transcription by binding repressor proteins (see above). As exemplified in Figure 2A, however, ribi promoters often display, at more upstream locations, binding sites for other TFs (like Abf1 and Tbf1).29,30,36 These factors thus likely participate to ribi gene transcription, but their precise function, mechanisms and cofactors at ribi promoters have never been investigated. Regulatory discrimination between RP, ribi and snoRNA genes. In yeast, genes belonging to RP and ribi regulons display very similar mRNA profiles in response to nutrient and stress conditions, with the TORC1 kinase likely acting as a master regulator ultimately influencing the activity of regulon-specific TFs.25 The different promoter architectures of RP and ribi genes, however, suggest regulatory discrimination, possibly related to the fact that ribosomal proteins, unlike ribi gene products, are stoichiometric components of the ribosome, requiring a more tight co-regulation with rRNA synthesis.37

The key RP gene activators Fhl1 and Ihf1 have not been reported to intervene in ribi gene transcription. On the other hand, transcriptional repressors recognizing the RRPE and PAC elements appear to play a key role in ribi gene regulation, while the only repressive mechanism for RP genes relies on Ifh1 dissociation upon competition with the paralog Crf1 repressor protein,16,38 which seems somehow dependent on genetic background.31 Another important issue is the different rate of transcription between RP and ribi genes. A recent and accurate measurement gives a figure of more than 30 mol/h of RNA Pol II engaged in productive transcription for RP genes, while the nascent transcription rate for ribi genes would be about four- to five-fold lower.39 Such impressive transcription rates imply an efficient nucleosome turnover in the coding region. Indeed, histone modifications enhancing nucleosome turnover, such as H3/H4 global acetylation and H3K4 tri-methylation, show a higher level in RP genes as compared with ribi genes.40 Apart from RP/ribi regulatory differences, there are even more basic issues of RP gene regulation that still deserve investigation, such as: the final targets of Ifh1 action, the mode of activation of the few RP genes not associated to Rap1 nor to Fhl1, the expression coordination between RP genes with different promoters (and even between identical RP gene copies whose promoters have diverged) and the role of Sfp1 and Hmo1 cofactors in TORdependent regulation.41 For what concerns the snoRNA gene family, the mode (and the existence itself) of snoRNA gene regulation (including a possible co-regulation with RP and ribi genes) is a totally unexplored issue that, if clarified, would also shed light on the actual role of snoRNA-dependent rRNA modifications.42 It is worth noting that eight snoRNA coding units in S. cerevisiae are located within introns of protein-coding genes (the prevailing type of organization in Metazoa). Interestingly, snoRNA host genes, both in yeast and in other eukaryotes, are generally involved in ribosome biogenesis or function. Such a location has the potential to ensure tight transcriptional co-regulation of intronencoded snoRNAs with other genes of the

ribosomal expression program.42 In some cases, the intron-embedded snoRNA could even impose a snoRNA-specific promoter architecture to the host gene. This possibility is illustrated in Figure 2B, showing the promoter organization of EFB1, IMD4 and TEF4, three S. cerevisiae ribi genes each accommodating an intronlocated snoRNA gene and displaying a snoRNA-like promoter, demarcated by a Tbf1 binding site. Evolutionary reshaping of transcriptional modules. In the last few years, the evolutionary dynamics of the ribosomal expression program has been systematically explored in fungi.30,43,44 A common emerging feature of ribosome-related regulons is their massive evolutionary reshaping, that involved profound changes in both cis and trans regulatory elements. Paradigmatic is the case of Tbf1 and its evolutionarily conserved binding motif, ARCCCTAA. In ascomycete fungi distantly related to S. cerevisiae, such as Candida albicans, Magnaporte grisea, Neurospora crassa and Schizosaccharomyces pombe, this motif was found to be associated to RP gene promoters in place of the Rap1 binding sites.43,44 The Tbf1 protein was later found to associate to RP gene promoters in C. albicans, where it cooperates with Cbf1 in RP gene transcription.45 Remarkably, Tbf1 binding sites are absent from RP gene promoters in S. cerevisiae and, conversely, no Rap1 binding sites occur in RP gene promoters in C. albicans. Such a complete substitution of a cis element-TF pair appears as an extreme example of transcription network flexibility. At the same time, however, it suggests that Rap1 and Tbf1 play similar, constitutive roles in promoter function. In particular, it is likely that they both ensure extremely high levels of transcription by contributing to nucleosome exclusion and/or efficient recruitment of the basal transcription machinery.35,46 It is worth noting that, at variance with the interchangeable Rap1 and Tbf1 factors, the Fhl1/Ihf1 TF pair is involved in, and dedicated to, RP gene regulation in both S. cerevisiae and C. albicans. Rap1 and Tbf1 thus behave as generalist TFs that have been flexibly adapted to different regulons over the course of evolution, while Fhl1 and Ihf1 can be counted among the specialist TFs that remain highly targeted to

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Figure 2. Upstream TF binding sites in ribi gene promoters. (A) GeneDoc visualization of Clustal X alignments of orthologous promoter regions from different Saccharomyces genomes for the ribi genes ARX1 (YDR101C ) and RRP7 (YCL031C ). ce, S. cerevisiae; pa, S. paradoxus; mi, S. mikatae; ba, S. bayanus; ku, S. kudriavzevii. Schematics of promoter organization are shown under the alignments. The reported distances are with respect to the TSS, while the alignments also include 5'-UTR sequences. (B) Tbf1 binding sites upstream of snoRNA-associated ribi genes. Schematics of promoter organization are shown. The reported distances are with respect to the TSS (right-pointing arrow). Introns are indicated by a simple line, with intron-located snoRNA genes as cyan boxes. The lengths of the first exons of IMD4 and TEF4 are not to scale.

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a specific regulon throughout evolution.30 The exploitation of Tbf1 as a TF in the snoRNA regulon29 corroborates the generalist character of Tbf1. The observation that both Rap1 (in S. cerevisiae ) and Tbf1 (in C. albicans) are required for Fhl1/Ihf1 recruitment to RP gene promoters30,31 further suggests the existence of a common set of interactions established by the two generalist TFs at promoters, although RP promoter activation also involves species-specific coactivators such as Cbf1 in C. albicans and Hmo1 in S. cerevisiae.30 Much less is known about the evolution of the ribi and snoRNA transcriptional networks in fungi. The combination of RRPE and PAC elements demarcates ribi gene promoters in almost all Hemiascomycetes, but the PAC could not be detected in other yeasts, such as S. pombe. Regulatory divergence thus occurred also for the ribi module, although probably with less flexibility compared to the RP regulon.43,44 As to the evolution of snoRNA promoter architecture, nothing is known except that a subset of C. albicans (and probably plant) snoRNA genes display Tbf1 binding motifs in their promoter regions.47 Exploring this issue will likely improve our (poor) understanding of snoRNA expression regulation. Promoter-telomere connection. Several proteins playing a key role in RP, ribi and snoRNA gene regulation (namely Rap1, Reb1 and Tbf1) share two remarkable common features: (1) they all display a myb-like DNA binding domain and (2) they are important components and regulators of the yeast telomeres.48 Abf1 is also both telomere-associated and involved in transcription of subsets of RP, ribi and snoRNA genes.2,29,36 This points to the existence of unexplored links between telomere regulation and gene transcription, particularly of ribosome-related genes. Very recent studies have shown that mammalian Rap1, known as a component of the shelterin complex at mammalian telomeres together with the Tbf1-related proteins Trf1 and Trf2, can be recruited, probably in a Trf2-mediated way, to extratelomeric genomic sites including many promoter regions, and can even influence NFB signalling.49 Such an evolutionarily conserved interface between telomere function and transcriptional regulation

suggests the existence of a totally unexplored regulatory crosstalk, possibly allowing to directly couple telomere length and cell growth.
Acknowledgements

Work in the authors lab was supported by the Italian Ministry of Education, University and Research (MIUR, PRIN grant to G.D. and R.N.) and by grants from Fondazione Cariparma (to G.D.) and Istituto PasteurFondazione Cenci Bolognetti (to R.N.).
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