Antagonistic Gcn5-Hda1 interactions revealed by mutations to the Anaphase Promoting Complex in yeast
© Islam et al; licensee BioMed Central Ltd. 2011
Received: 20 January 2011
Accepted: 8 June 2011
Published: 8 June 2011
Histone post-translational modifications are critical for gene expression and cell viability. A broad spectrum of histone lysine residues have been identified in yeast that are targeted by a variety of modifying enzymes. However, the regulation and interaction of these enzymes remains relatively uncharacterized. Previously we demonstrated that deletion of either the histone acetyltransferase (HAT) GCN5 or the histone deacetylase (HDAC) HDA1 exacerbated the temperature sensitive (ts) mutant phenotype of the Anaphase Promoting Complex (APC) apc5 CA allele. Here, the apc5 CA mutant background is used to study a previously uncharacterized functional antagonistic genetic interaction between Gcn5 and Hda1 that is not detected in APC5 cells.
Using Northerns, Westerns, reverse transcriptase PCR (rtPCR), chromatin immunoprecipitation (ChIP), and mutant phenotype suppression analysis, we observed that Hda1 and Gcn5 appear to compete for recruitment to promoters. We observed that the presence of Hda1 can partially occlude the binding of Gcn5 to the same promoter. Occlusion of Gcn5 recruitment to these promoters involved Hda1 and Tup1. Using sequential ChIP we show that Hda1 and Tup1 likely form complexes at these promoters, and that complex formation can be increased by deleting GCN5.
Our data suggests large Gcn5 and Hda1 containing complexes may compete for space on promoters that utilize the Ssn6/Tup1 repressor complex. We predict that in apc5 CA cells the accumulation of an APC target may compensate for the loss of both GCN5 and HDA1.
Eukaryotic genetic information is packaged into chromatin, a highly organized and dynamic protein-DNA complex. The fundamental unit of chromatin, the nucleosome, is an octameric structure composed of two copies of each of the four core histones (an H3/H4 tetramer and two H2A/H2B dimers), surrounded by approximately 146 bp of DNA [1, 2]. Many cellular processes depend on modifications of both DNA and histones within nucleosomes [3, 4]. Modification of chromatin by histone acetyltransferases (HATs) and histone deacetylases (HDACs) play key roles in transcriptional regulation [5–9]. Post-translational acetylation of the highly conserved lysines within the N-terminal tail domains of the core histones is strongly correlated with transcriptional activation [5, 10]. Although the precise mechanisms by which histone acetylation alters transcription are poorly understood [9–12], there is tremendous pressure to understand these mechanisms, as impaired histone modification is linked to many disease states .
The study of HAT and HDAC recruitment to promoters and their interaction with activators and repressors are essential for a better understanding of gene regulation. HATs and HDACs modify histones enzymatically throughout the genome . Histone acetylation potentially regulates transcription by manipulating the higher-order folding properties of the chromatin fiber [15–17]. General control nonderepressible 5 (Gcn5)  was the first identified HAT and exists as the catalytic subunit in multiple high molecular weight complexes in yeast, including SAGA (Spt-Ada-Gcn5-Acetyltransferase), SLIK (SAGA-like), ADA (transcriptional ADAaptor), and the smaller HAT-A2 complex [19–23]. As part of the evolutionarily conserved SAGA complex, Gcn5 predominantly acetylates nucleosomal H3 lysines K9, K18, and K27 . Defects in human SAGA subunits are associated with multiple disorders, including neurological diseases and aggressive cancers [25, 26]. Gcn5 is a direct target for recruitment by transcriptional activators in vitro [27, 28] and in vivo , which results in the acetylation of nearby histones . Elongation of the transcripts initiated by Gcn5-containing complexes is carried out by the Elongator complex, which utilizes Elp3 as its primary HAT [30, 31]. Cell cycle specific roles for Gcn5 have been reported, as recruitment of Gcn5 to a set of genes that are expressed in late mitosis requires SWI/SNF remodelling activity . Furthermore, Gcn5 displays an overlapping pattern of localization with several HDACs [24, 33, 34]. Acetylation microarrays have shown that Rpd3 and Hda1 are the principal HDACs in yeast, affecting numerous promoters throughout the genome with little overlap between promoters [10, 35]. Hda1, an evolutionary conserved HDAC, which deacetylates mainly histones H2B and H3 [36, 37], is recruited to promoters via utilization of different Tup1/Ssn6 domains [38–40], resulting in local deacetylation. HDAC recruitment may form a positive feedback loop to repress transcription locally and facilitate the spreading of Tup1 into adjacent regions . Tup1-mediated repression requires the deacetylation of histones within promoters [42–44], which may require direct recruitment of HDACs [36, 45, 46]. Overall, the mechanisms of Tup1/Ssn6-mediated transcriptional repression can be classified into 3 classes: (i) direct interaction with the activator; (ii) repression by changing chromatin structure; and (iii) interaction with the general transcription machinery [47, 48]. It appears that different groups of genes have developed different strategies to utilize Tup1/Ssn6, enabling it to function as a global repressor.
Our work has linked the Anaphase Promoting Complex (APC), an evolutionarily conserved 13 subunit complex in yeast that is critical for mitotic progression and G1 maintenance [49–52], with chromatin assembly and histone acetylation through genetic interactions with chromatin assembly factor (CAF), HAT and HDAC mutants [53–57]. The APC is a ubiquitin-protein ligase (E3) that targets proteins that block the initiation of anaphase (Pds1) and mitotic exit (Clb2) for degradation. Various regulators govern APC activity in positive and negative manners, from phosphorylation and transcriptional control of APC subunits, to sequestration of APC activators [58–63]. For example, protein kinase A (a complex of Bcy1, Tpk1, Tpk2 and Tpk3) and Mad2 inhibit APC activity through phosphorylation and subunit sequestration, respectively. Activating phosphorylation is supplied by the polo-like kinase (Cdc5) and Cdc28. Furthermore, Cdc20, inhibited by a Mad2-dependent mechanism, binds and activates the APC to promote the metaphase/anaphase transition, while Cdh1, another APC-binding partner, drives APC-dependent mitotic exit. Previous studies by our group have expanded the APC's functional repertoire by showing that the mutant APC subunit allele, apc5 CA , genetically interacted with deletions of the HAT encoding genes GCN5 and ELP3 . Strains harboring the apc5 CA gcn5 Δ or the apc5 CA elp3 Δ mutations had severely restricted growth at elevated temperatures compared to the single mutants. This interaction implies that the APC and these HATs positively interact, but a negative feedback loop appears apparent, as G1-specific Gcn5 instability was reduced in APC mutant cells. An additional synergistic genetic interaction between hda1 Δ and apc5 CA was also observed, suggesting that the APC interacts positively with the HDAC Hda1 . The study presented here focuses on a novel antagonistic relationship between gcn5 Δ and hda1 Δ that is revealed in apc5 CA , but not APC5 cells. We provide further evidence that the APC works with multiple histone modifiers to drive cell cycle progression.
gcn5 Δ/hda1 Δ interactions revealed in an APC mutant background
To examine whether Hda1 positively interacted with the APC, we expressed galactose driven HDA1 carrying a C-terminal HA tag (GAL pro HDA1-HA) at low levels in WT, apc5 CA and gcn5 Δ cells by using glucose as a carbon source (Figure 1B). Recently, we observed that mRNA levels of GAL pro GCN5-HA were elevated 100-fold when grown on 2% glucose and 900-fold when grown on 2% galactose . However, Gcn5-HA protein expression remained low even though GCN5-HA mRNA was 100-fold elevated when grown on 2% glucose. As shown with GCN5 , low-level GAL pro HDA1-HA expression improved apc5 CA growth (Figure 1B). This is not necessarily a general feature of histone modifying proteins, as deletion or overexpression of the HAT HPA2 had little effect on apc5 CA cells (Figure 1B) . Although the yeast Hpa2 has not yet been shown to acetylate histones in vivo, a bacterial acetyltransferase that does acetylate eukaryotic histones is most closely related to Hpa2, and Hpa2 does acetylate H3 in vitro [65, 66]. Moreover, Hpa2 appears to be active, as overexpression reduces growth of gcn5 Δ cells, whereas expression on glucose improves growth of apc5 CA cells (Figure 1B).
A further connection between Gcn5 and Apc5 was observed by the rescue of GAL pro APC5-HA overexpression toxicity by deletion of GCN5 (Figure 1B). It is unlikely that Apc5 protein levels induced from the GAL promoter are compromised in gcn5 Δ cells, as expression of HPA2 and HDA1 from the GAL promoter reduces gcn5 Δ growth. Overexpression of APC5 from the CUP1 promoter also reduced yeast replicative lifespan . Rescue of APC5 toxicity by GCN5 deletion is consistent with our recently proposed hypothesis that Gcn5 is required for APC activity, and may provide an explanation as to why GCN5  and HDA1 (Figure 1B) overexpression is toxic, considering that overabundance of Apc5 is detrimental to cells.
Next, we asked whether mutations to APC5 influenced acetylation of histone H3 lysine 9 or 14 (H3K9/14) in gcn5 Δ and hda1 Δ cells. Gcn5 appears to play a greater role on H3K9, compared to H3K14, whereas loss of HDA1 results in increased acetylation of both H3K9 and H3K14 (Figure 1C). The apc5 CA background did not change the acetylation status of H3K9/14 in gcn5 Δ or hda1 Δ cells, suggesting the apc5 CA background may be revealing an effect other than global histone H3 acetylation. H3K9Ac was reduced in gcn5 Δ, apc5 CA gcn5 Δ and apc5 CA gcn5 Δ hda1 Δ cells, but not in gcn5 Δ hda1 Δ cells. The ability to acetylate H3K9 in gcn5 Δ hda1 Δ cells indicates that on a global level, other HATs can use H3K9 as a substrate. However, at the gene level, deletion of GCN5 was previously shown to reverse histone hyperacetylation at the PHO5 promoter when HDA1 was deleted . Therefore, we tested whether transcript levels are influenced by apc5 CA in gcn5 Δ or hda1 Δ cells.
The apc5 CA allele increases transcript levels in hda1 Δ cells
Increased PDS1 transcripts in apc5 CA hda1 Δ cells correlates with increased promoter acetylation
Consistent with our observations that transcript levels of BCY1 and PDS1 increase in apc5 CA hda1 Δ cells, we detected increased BCY1 and PDS1 promoter acetylation in these cells, specifically at 37°C. Transcript levels and promoter acetylation are both increased with PDS1 at 37°C in apc5 CA hda1 Δ cells. However, we note some differences in the patterns observed. For example, BCY1 transcripts are not elevated in apc5 CA hda1 Δ cells at 37°C while promoter acetylation is. This may reflect the complex nature of the factors assembled at promoters that is not addressed in this study.
Gcn5 promoter occupancy increases in the absence of Hda1
Next we asked whether promoter occupancy by Gcn5 correlated with gene expression and promoter acetylation. GAL pro GCN5-HA was induced in gcn5 Δ and gcn5 Δ hda1 Δ cells so that the only Gcn5 expressed was HA tagged. gcn5 Δ cells expressing GAL pro GCN5-HA grew like WT (data not shown), and were considered the WT control for this experiment. ChIP was performed in lysates prepared from these cells. Control ChIPs were performed using untagged lysates (data not shown), and reactions without antibody, neither of which produced PCR products. Primers against the 5', middle, and 3' regions of CDC20 demonstrated that Gcn5-HA recruitment was most prominent at the promoter and was reduced 5' to 3' (data not shown). We found that in HDA1 cells expressing GCN5-HA, very little Gcn5-HA was present at the promoters tested compared with the RDN1 promoter (Figures 4C and 4D). In hda1 Δ GCN5-HA cells, however, increased Gcn5-HA promoter recruitment was observed. The increases observed were slight except for the CDC20 promoter. Promoter acetylation also increased in hda1 Δ cells, consistent with increased recruitment of Gcn5. These observations present the possibility that i) increased promoter H3K9/14 acetylation in hda1 Δ cells is due to increased Gcn5-HA promoter recruitment; and/or ii) Hda1 may block access of Gcn5 to promoters.
Tup1 occludes Gcn5 promoter occupancy
To distinguish between these possibilities, we predicted that if Tup1 and Hda1 work together, then deletion of TUP1 in apc5 CA cells should have the same synergistic effects as an HDA1 deletion. Our results show that deletion of TUP1 impairs the apc5 CA phenotype (Figure 6C), similar to an hda1 Δ mutation. This suggests that both Hda1 and Tup1 perform a function that is beneficial to APC activity. However, it does not necessarily indicate they work together to perform this task.
Hda1 and Tup1 likely interact at promoters, which can be inhibited by Gcn5
Novel Gcn5/Hda1 antagonistic functional interactions are revealed when APC activity is compromised
The work presented here provides evidence to support a model in which the HAT Gcn5 and the HDAC Hda1 functionally interact at promoters to determine transcriptional readouts (Figure 8). In otherwise WT cells, mutations to GCN5 or HDA1 do not create significant growth defects, whereas in apc5 CA cells, these same mutations produce severe ts growth defects (Figure 1A). The focus of this study was to characterize an antagonistic functional gcn5 Δ/hda1 Δ interaction revealed in the apc5 CA background, as the severe apc5 CA gcn5 Δ and apc5 CA hda1 Δ ts defects are suppressed in apc5 CA gcn5 Δ hda1 Δ cells. Growth phenotypes associated with deletion of GCN5 have been shown in two separate Synthetic Genetic Array (SGA) genome-wide screens to be suppressed by deletion of HDA1 [76, 77]. However, spot dilution analysis of the gcn5 Δ and hda1 Δ cells on YPD did not reveal any phenotypes , as shown in our study (Figure 1A). Thus, the gcn5 Δ hda1 Δ antagonistic interaction is not apparent under normal growth conditions, such as on YPD, but under conditions imposed by the SGA screen (selective media, for example), the antagonistic interaction can be exposed. The influence of the apc5 CA allele on this interaction was investigated. The apc5 CA allele had little effect on global histone H3 acetylation status in gcn5 Δ and hda1 Δ cells, but did cause the increase of BCY1 and PDS1 transcripts in hda1 Δ cells (Figures 1C, 3). Both Bcy1 and Pds1 proteins antagonize APC activity and may be involved in the enhanced growth defect when APC is mutated. Therefore, in apc5 CA cells, it may be the inappropriate expression of inhibitory transcripts that are paramount to synergistic apc5 CA gcn5 Δ and apc5 CA hda1 Δ phenotypes.
A molecular mechanism explaining the Gcn5/Hda1 interaction likely involves competition for Tup1 binding. We observed that in cells lacking HDA1 or TUP1, Gcn5 recruitment at our tested promoters was increased (Figures 4 and 6). On the other hand, deletion of GCN5 increased Hda1-Tup1 physical interactions at promoters (Figure 7). A competition between Hda1 and Gcn5 for Tup1 binding is a possibility worth considering, as both Hda1 and Gcn5 have been shown to physically interact with Tup1 [36, 73–75]. However, in gcn5 hda1 Δ cells this mechanism would not be possible. In addition to the accumulation of Gcn5 in apc5 CA cells, we observed that Elp3 also accumulates when the ubiquitin system is compromised (Figures 4A, B). We previously demonstrated that gcn5 Δ and elp3 Δ deletions impair apc5 CA defects, that GCN5 and ELP3 overexpression stalls the cell cycle in G1, and that Gcn5 G1-specific instability is reversed in APC mutants . Thus, when apc5 CA is combined with gcn5 Δ hda1Δ, an APC target likely accumulates that creates novel transcripts that allow bypass of the severe ts defects observed in the double mutants. Elp3 is an attractive candidate since it is involved in elongating transcripts initiated by Gcn5 containing complexes . A global transcript analysis is likely required to follow this further. Our previous work suggests that the apc5 CA phenotype is sensitive to global transcript levels .
Hda1-dependent occlusion of Gcn5 from promoters requires Tup1
Several reports describe the recruitment of the Tup1/Ssn6 repressor complex to DNA via interactions with multiple partners [41, 48, 68]. Once recruited, Tup1 then contacts H3 and H4 N-terminal tails . Mechanisms employed to recruit Tup1/Ssn6 to promoters by the various individual interacting partners appears to be complex, seems to vary, and may have overlapping roles. Gcn5-HA recruitment to the tested promoters was increased in hda1 Δ, tup1 Δ and ssn6 Δ cells (Figure 6; data not shown), indicating that the interaction of Hda1 with the Tup1/Ssn6 repressor complex is necessary to block access to Gcn5. Tup1 and Hda1 did indeed co-immunoprecipitate while bound to the same promoters, as shown by sequential ChIP (Figure 7). We find it unlikely that Tup1 and Hda1 are simply associating independently at adjacent sequences within the 200-basepair DNA PCR fragment, since they have been shown to interact previously , and are part of large complexes [19–23], but we cannot discount this possibility. However, we observed that in gcn5 Δ cells, Hda1-Tup1 association increased at some promoters (PDS1 and BCY1), suggesting Gcn5 opposes complex formation. The mechanism of action that Gcn5 uses to block Hda1-Tup1 association remains unclear. Previous reports indicating that Tup1 is capable of recruiting and interacting with Gcn5/SAGA at promoters [73–75] suggest it is possible that Gcn5 and Hda1 may compete for Tup1 interaction. The scenario for recruiting either Gcn5 or Hda1 would differ, implying other proteins may be involved in deciding whether Gcn5 or Hda1 gain access. We were unable to observe complex formation between Gcn5-TAP and Hda1-HA in whole cell lysates (data not shown), indicating possible exchange of Gcn5 and Hda1 at Tup1 complexes does not require Gcn5-Hda1 association. It is also possible that Gcn5-Hda1 physical interactions are transient and promoter specific, therefore may not be detectable using the methods applied here. Nonetheless, support for our model was provided by reports describing recruitment of Gcn5 to promoters by the Tup1/Ssn6 complex under osmotic stress conditions [40, 74], indicating that Tup1/Ssn6 may be a transcriptional activator under certain conditions.
The results presented in this manuscript provide evidence for a complex network of interactions between a mitotic/G1 cell cycle regulator (the APC), and antagonistic interplay between a HAT (Gcn5), and an HDAC (Hda1). Gcn5 is known to function during mitosis [32, 57, 79, 80]. Data on the role Hda1 plays in cell cycle progression is limited, but Hda1 may provide some function to ensure histones are deacetylated prior to passage through mitosis . It is noteworthy that Gcn5 and Hda1 expression is temporally regulated during the cell cycle (microarray data compiled at Saccharomyces Genome Database), providing insight into how the potential competition for Tup1 binding could be regulated. APC mutations cause cell cycle progression to stall during mitosis, potentially skewing the equilibrium between Gcn5 and Hda1 promoter recruitment if the cell cycle does indeed influence Hda1 and Gcn5 recruitment. Future work will focus on identifying the molecular mechanisms regulating how cell cycle progression influences chromatin dynamics. Chromosome synthesis and segregation defects are widely associated with human disease, thus continued work into furthering our understanding of this process is vital.
Media, yeast strains, plasmids and general methods
Yeast strains used in this study
MATα ade2 his3 Δ200 lys2 Δ201 ura 3-52
MATa ade2 his3 Δ200 lys2 Δ201 ura3-52
MATa his3 Δ1 leu2 Δ met15 Δ ura3 Δ tup1 Δ::kanMX6
MATa his3 Δ1 leu2 Δ met15 Δ ura3 Δ ssn6 Δ::kanMX6
MATa ade2 his3 Δ200 lys2 Δ201 ura3-52
MAT(?) ade2 his3 leu2 lys2(?) ura3 apc5 CA -PA::His5 + tup1 Δ::kanMX6
MAT(?) ade2 his3 leu2 lys2(?) ura3 hda1 Δ::kanMX6
MAT(?) ade2 his3 leu2 lys2(?) ura3 apc5 CA -PA::His5 + hda1 Δ::kanMX6
MAT(?) ade2 his3 leu2 lys2(?) ura3 gcn5 Δ::kanMX6
MAT(?) ade2 his3 leu2 lys2(?) ura3 apc5 CA -PA::His5 + gcn5 Δ::kanMX6
MAT(?) ade2 his3 leu2 lys2(?) ura3 gcn5 Δ::kanMX6 hda1 Δ::kanMX6
MAT(?) ade2 his3 leu2 lys2(?) ura3 apc5 CA -PA::His5 + gcn5 Δ::kanMX6 hda1 Δ::kanMX6
MATa his3 Δ1 leu2 Δ met15 Δura3 Δ rpn10 Δ::kanMX6
MATa his3 Δ1 leu2 Δ met15 Δ ura3 Δ GCN5-TAP::HIS3
as YTH1235, with GCN5-TAP::HIS3
as YTH5, with tup1 Δ::kanMX6
as YTH5, with ssn6 Δ::kanMX6
MAT(?) ade2 his3 leu2 lys2(?) ura3 gcn5 Δ::kanMX6 ssn6 Δ::kanMX6
MAT(?) ade2 his3 leu2 lys2(?) ura3 gcn5 Δ::kanMX6 tup1 Δ::kanMX6
MATa his3 Δ1 leu2 Δ met15 Δ ura3 Δ APC5-TAP::HIS3 rpn10 Δ::kanMX6
Plasmids used in this study
URA3 CEN ARS
GAL pro -APC5-HA
2μ GAL10 pro -APC5-HA URA3
GAL pro -GCN5-HA
2μ GAL10 pro -GCN5-HA URA3
GAL pro -HDA1-HA
2μ GAL10 pro -HDA1-HA URA3
GAL pro -HPA2-HA
2μ GAL10 pro -HDA1-HA URA3
2μ CUP1 pro -TUP1 URA3
2μ CUP1 pro -TUP1 URA3
Primers generated for the Northern analysis
Reverse transcriptase PCR (rtPCR)
Primers generated for the ChIP analysis
Chromatin immunoprecipitation (ChIP)
ChIP was performed essentially as described elsewhere [82, 83] with the following modifications: DNA fragment size achieved by sonication was 500-1000 bp, and 100 μg of protein lysate was used for each IP. Protein concentration was determined by a Bradford protein assay. 5 μg of ChIP grade rabbit polyclonal anti-acetyl-H3K9/14 (Upstate Biotechnology), rabbit polyclonal anti-H3 (Abcam), rabbit polyclonal HA antibody (Abcam), and rabbit polyclonal GST antibody (Abcam) were used for IP. One-tenth of the total volume of lysate was used as input for each sample. Sequential ChIP was performed as previously described . In sequential ChIP experiements, the immune complexes were eluted by incubation for 30 minutes at 37°C in 10 mM DTT. After centrifugation, the supernatant was diluted 25 times with ChIP dilution buffer (1% Triton X-100, 2 mM EDTA, 150 mM NaCl, 20 mM Tris-HCl [pH 8.1]) and subjected again to ChIP using a different antibody. In this experiment, HA antibody was applied first, followed by GST antibody. Cross-linking of the immune complex was reversed by adding NaCl to a final concentration of 0.3 M and incubated overnight at 65°C. Samples were treated first with 1 μg/μl RNaseA (Millipore [formerly Upstate]) for 30 minutes at 37°C, followed by 1 μg/μl proteinase K (Millipore [formerly Upstate]) at 45°C for 1 hour. DNA was purified by chromatography on QIAquick columns, and eluted with elution buffer (PCR purification kit, Qiagen). PCR was performed for semiquantitative determination by standard end point PCR. 1 μl DNA was used for PCR, and the reaction continued to the predetermined mid-linear range for each primer set. The end point PCR product was resolved on a 1% agarose gel and visualized by ethidium bromide. Two independent experiments were performed for each ChIP. The gel bands from each experiment were analyzed by ImageJ, and the means and standard error were plotted for graphical representation. For time course experiments, 200 ml cultures were induced at a final concentration of 4% galactose. Samples (20 ml) were immediately removed, and again after 1, 3 and 5 hours. The 20 ml samples were in duplicate for Western and ChIP analysis.
AI was supported by Post-Doctoral Fellowships from the Saskatchewan Health Research Foundation (SHRF), and from the Canadian Institutes for Health Research-Regional Partnership Program (CIHR-RPP). ELT was supported by Graduate Scholarships from the College of Graduate Studies at the U of S. Deletion mutants and plasmids were kindly provided by Dr. W. Xiao (University of Saskatchewan). We thank members of the Harkness lab, Ata Ghavidel and Spike Postnikoff, for careful reading of the manuscript and for providing insightful suggestions. Funding was generously provided to TAAH through a CIHR Operating Grant and a New Investigator Award from the Canadian Foundation for Innovation (CFI).
- Tyler JK: Chromatin assembly. Cooperation between histone chaperones and ATP-dependent nucleosome remodeling machines. Eur J Biochem 2002, 269: 2268–2274. 10.1046/j.1432-1033.2002.02890.xView ArticlePubMedGoogle Scholar
- Verreault A: De novo nucleosome assembly: new pieces in an old puzzle. Genes Dev 2000, 14: 1430–8.PubMedGoogle Scholar
- Hagmann M: How chromatin changes its shape. Science 1999, 285: 1200–1203. 10.1126/science.285.5431.1200View ArticlePubMedGoogle Scholar
- Strahl BD, Allis CD: The language of covalent histone modifications. Nature 2000, 403: 41–45. 10.1038/47412View ArticlePubMedGoogle Scholar
- Brown CE, Lechner T, Howe L, Workman JL: The many HATs of transcription coactivators. Trends Biochem Sci 2000, 25: 15–19. 10.1016/S0968-0004(99)01516-9View ArticlePubMedGoogle Scholar
- Cheung WL, Briggs SD, Allis CD: Acetylation and chromosomal functions. Curr Opin Cell Biol 2000, 12: 326–333. 10.1016/S0955-0674(00)00096-XView ArticlePubMedGoogle Scholar
- Han Q, Lu J, Duan J, Su D, Hou X, Li F, Wang X, Huang B: Gcn5- and Elp3-induced histone H3 acetylation regulates hsp70 gene transcription in yeast. Biochem J 2008, 409: 779–788. 10.1042/BJ20070578View ArticlePubMedGoogle Scholar
- Sterner DE, Berger SL: Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev 2000, 64: 435–459. 10.1128/MMBR.64.2.435-459.2000PubMed CentralView ArticlePubMedGoogle Scholar
- Struhl K: Histone acetylation and transcriptional regulatory mechanisms. Genes Dev 1998, 12: 599–606. 10.1101/gad.12.5.599View ArticlePubMedGoogle Scholar
- Kurdistani SM, Grunstein M: Histone acetylation and deacetylation in yeast. Nat Rev Mol Cell Biol 2003, 4: 276–284. 10.1038/nrm1075View ArticlePubMedGoogle Scholar
- Paranjape SM, Kamakaka RT, Kadonaga JT: Role of chromatin structure in the regulation of transcription by RNA polymerase II. Annu Rev Biochem 1994, 63: 265–297. 10.1146/annurev.bi.63.070194.001405View ArticlePubMedGoogle Scholar
- Krebs JE: Moving marks: dynamic histone modifications in yeast. Mol Biosyst 2007, 3: 590–597. 10.1039/b703923aView ArticlePubMedGoogle Scholar
- Khan SN, Khan AU: Role of histone acetylation in cell physiology and diseases: An update. Clin Chim Acta 2010, 411: 1401–1411. 10.1016/j.cca.2010.06.020View ArticlePubMedGoogle Scholar
- Vogelauer M, Wu J, Suka N, Grunstein M: Global histone acetylation and deacetylation in yeast. Nature 2000, 408: 495–498. 10.1038/35044127View ArticlePubMedGoogle Scholar
- Kan PY, Lu X, Hansen JC, Hayes JJ: The H3 tail domain participates in multiple interactions during folding and self-association of nucleosome arrays. Mol Cell Biol 2007, 27: 2084–2091. 10.1128/MCB.02181-06PubMed CentralView ArticlePubMedGoogle Scholar
- Kan PY, Caterino TL, Hayes JJ: The H4 tail domain participates in intra- and internucleosome interactions with protein and DNA during folding and oligomerization of nucleosome arrays. Mol Cell Biol 2009, 29: 538–546. 10.1128/MCB.01343-08PubMed CentralView ArticlePubMedGoogle Scholar
- Shogren-Knaak M, Ishii H, Sun JM, Pazin MJ, Davie JR, Peterson CL: Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 2006, 311: 844–847. 10.1126/science.1124000View ArticlePubMedGoogle Scholar
- Lucchini G, Hinnebusch AG, Chen C, Fink GR: Positive regulatory interactions of the HIS4 gene of Saccharomyces cerevisiae . Mol Cell Biol 1984, 4: 1326–1333.PubMed CentralPubMedView ArticleGoogle Scholar
- Brownell JE, Zhou J, Ranalli T, Kobayashi R, Edmondson DG, Roth SY, Allis CD: Tetrahymena histone acetyltransferase A: a transcriptional co-activator linking gene expression to histone acetylation. Cell 1996, 84: 843–851. 10.1016/S0092-8674(00)81063-6View ArticlePubMedGoogle Scholar
- Grant PA, Duggan L, Côté J, Roberts SM, Brownell JE, Candau R, Ohba R, Owen-Hughes T, Allis CD, Winston F, Berger SL, Workman JL: Yeast Gcn5 functions in two multisubunit complexes to acetylate nucleosomal histones: characterization of an Ada complex and the SAGA (Spt/Ada) complex. Genes Dev 1997, 11: 1640–1650. 10.1101/gad.11.13.1640View ArticlePubMedGoogle Scholar
- Baker SP, Grant PA: The SAGA continues: expanding the cellular role of a transcriptional co-activator complex. Oncogene 2007, 26: 5329–5340. 10.1038/sj.onc.1210603PubMed CentralView ArticlePubMedGoogle Scholar
- Pray-Grant MG, Schieltz D, McMahon SJ, Wood JM, Kennedy EL, Cook RG, Workman JL, Yates JR, Grant PA: The novel SLIK histone acetyltransferase complex functions in the yeast retrograde response pathway. Mol Cell Biol 2002, 22: 8774–8786. 10.1128/MCB.22.24.8774-8786.2002PubMed CentralView ArticlePubMedGoogle Scholar
- Sendra R, Tse C, Hansen JC: The yeast histone acetyltransferase A2 complex, but not free Gcn5p, binds stably to nucleosomal arrays. J Biol Chem 2000, 275: 24928–24934. 10.1074/jbc.M003783200View ArticlePubMedGoogle Scholar
- Johnsson AE, Wright AP: The role of specific HAT-HDAC interactions in transcriptional elongation. Cell Cycle 2010, 9: 467–71. 10.4161/cc.9.3.10543View ArticlePubMedGoogle Scholar
- McCullough SD, Grant PA: Histone acetylation, acetyltransferases, and ataxia-alteration of histone acetylation and chromatin dynamics is implicated in the pathogenesis of polyglutamine-expansion disorders. Adv Protein Chem Struct Biol 2010, 79: 165–203.PubMed CentralView ArticlePubMedGoogle Scholar
- Koutelou E, Hirsch CL, Dent SY: Multiple faces of the SAGA complex. Curr Opin Cell Biol 2010, 22: 374–382. 10.1016/j.ceb.2010.03.005PubMed CentralView ArticlePubMedGoogle Scholar
- Utley RT, Ikeda K, Grant PA, Cote J, Steger DJ, Eberharter A, John S, Workman JL: Transcriptional activators direct histone acetyltransferase complexes to nucleosomes. Nature 1998, 394: 498–502. 10.1038/28886View ArticlePubMedGoogle Scholar
- Rosaleny LE, Ruiz-Garcia AB, Garcia-Martinez J, Perez-Ortin JE, Tordera V: The Sas3p and Gcn5p histone acetyltransferases are recruited to similar genes. Genome Biol 2007, 8: R119. 10.1186/gb-2007-8-6-r119PubMed CentralView ArticlePubMedGoogle Scholar
- Bhaumik SR, Raha T, Aiello DP, Green MR: In vivo target of a transcriptional activator revealed by fluorescence resonance energy transfer. Genes Dev 2004, 18: 333–343. 10.1101/gad.1148404PubMed CentralView ArticlePubMedGoogle Scholar
- Wittschieben BO, Otero G, de Bizemont T, Fellows J, Erdjument-Bromage H, Ohba R, Li Y, Allis CD, Tempst P, Svejstrup JQ: A novel histone acetyltransferase is an integral subunit of elongating RNA polymerase II holoenzyme. Mol Cell 1999, 4: 123–128. 10.1016/S1097-2765(00)80194-XView ArticlePubMedGoogle Scholar
- Wittschieben BO, Fellows J, Du W, Stillman DJ, Svejstrup JQ: Overlapping roles for the histone acetyltransferase activities of SAGA and elongator in vivo . EMBO J 2000, 19: 3060–3068. 10.1093/emboj/19.12.3060PubMed CentralView ArticlePubMedGoogle Scholar
- Krebs JE, Fry CJ, Samuels ML, Peterson CL: Global role for chromatin remodeling enzymes in mitotic gene expression. Cell 2000, 102: 587–598. 10.1016/S0092-8674(00)00081-7View ArticlePubMedGoogle Scholar
- Wirén M, Silverstein RA, Sinha I, Walfridsson J, Lee HM, Laurenson P, Pillus L, Robyr D, Grunstein M, Ekwall K: Genome wide analysis of nucleosome density histone acetylation and HDAC function in fission yeast. EMBO J 2005, 24: 2906–2918. 10.1038/sj.emboj.7600758PubMed CentralView ArticlePubMedGoogle Scholar
- Dubief MD, Sinha I, Billai FF, Bonilla C, Wright A, Grunstein M, Ekwall K: Specific functions for the fission yeast Sirtuins Hst2 and Hst4 in gene regulation and retrotransposon silencing. EMBO J 2007, 26: 2477–2488. 10.1038/sj.emboj.7601690View ArticleGoogle Scholar
- Kurdistani SK, Robyr D, Tavazoie S, Grunstein M: Genome-wide binding map of the histone deacetylase Rpd3 in yeast. Nat Genet 2002, 31: 248–254. 10.1038/ng907View ArticlePubMedGoogle Scholar
- Wu J, Suka N, Carlson M, Grunstein M: TUP1 utilizes histone H3/H2B-specific HDA1 deacetylase to repress gene activity in yeast. Mol Cell 2001, 7: 117–126. 10.1016/S1097-2765(01)00160-5View ArticlePubMedGoogle Scholar
- Robyr D, Suka Y, Xenarios I, Kurdistani SK, Wang A, Suka N, Grunstein M: Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases. Cell 2002, 109: 437–446. 10.1016/S0092-8674(02)00746-8View ArticlePubMedGoogle Scholar
- Komachi K, Redd M, Johnson A: The WD repeats of Tup1 interact with the homeo domain protein alpha 2. Genes Dev 1994, 8: 2857–2867. 10.1101/gad.8.23.2857View ArticlePubMedGoogle Scholar
- Tzamarias D, Struhl K: Distinct TPR motifs of Cyc8 are involved in recruiting the Cyc8-Tup1 corepressor complex to differentially regulated promoters. Genes Dev 1995, 9: 821–831. 10.1101/gad.9.7.821View ArticlePubMedGoogle Scholar
- Kobayashi Y, Inai T, Mizunuma M, Okada I, Shitamukai A, Hirata D, Miyakawa T: Identification of Tup1 and Cyc8 mutations defective in the responses to osmotic stress. Biochem Biophys Res Commun 2008, 368: 50–55. 10.1016/j.bbrc.2008.01.033View ArticlePubMedGoogle Scholar
- Zhang Z, Reese JC: Redundant Mechanisms Are Used by Ssn6-Tup1 in Repressing Chromosomal Gene Transcription in Saccharomyces cerevisiae . J Biol Chem 2004, 279: 39240–39250. 10.1074/jbc.M407159200View ArticlePubMedGoogle Scholar
- Bone JR, Roth SY: Recruitment of the yeast Tup1p-Ssn6p repressor is associated with localized decreases in histone acetylation. J Biol Chem 2001, 276: 1808–1813.View ArticlePubMedGoogle Scholar
- Deckert J, Struhl K: Histone acetylation at promoters is differentially affected by specific activators and repressors. Mol Cell Biol 2001, 21: 2726–2735. 10.1128/MCB.21.8.2726-2735.2001PubMed CentralView ArticlePubMedGoogle Scholar
- Davie JK, Trumbly RJ, Dent SY: Histone-dependent association of Tup1-Ssn6 with repressed genes in vivo . Mol Cell Biol 2002, 22: 693–703. 10.1128/MCB.22.3.693-703.2002PubMed CentralView ArticlePubMedGoogle Scholar
- Watson AD, Edmondson DG, Bone JR, Mukai Y, Yu Y, Du W, Stillman DJ, Roth SY: Ssn6-Tup1 interacts with class I histone deacetylases required for repression. Genes Dev 2000, 14: 2737–2744. 10.1101/gad.829100PubMed CentralView ArticlePubMedGoogle Scholar
- Davie JK, Edmondson DG, Coco CB, Dent SY: Tup1-Ssn6 interacts with multiple class I histone deacetylases in vivo . J Biol Chem 2003, 278: 50158–50162. 10.1074/jbc.M309753200View ArticlePubMedGoogle Scholar
- Smith RL, Johnson AD: Turning genes off by Ssn6-Tup1: a conserved system of transcriptional repression in eukaryotes. Trends Biochem Sci 2000, 25: 325–330. 10.1016/S0968-0004(00)01592-9View ArticlePubMedGoogle Scholar
- Malavé TM, Dent SY: Transcriptional repression by Tup1-Ssn6. Biochem. Cell Biol 2006, 84: 437–443.Google Scholar
- Harper JW, Burton JL, Solomon MJ: The anaphase-promoting complex: it's not just for mitosis any more. Genes Dev 2002, 16: 2179–2206. 10.1101/gad.1013102View ArticlePubMedGoogle Scholar
- Manchado E, Eguren M, Malumbres M: The anaphase-promoting complex/cyclosome (APC/C): cell-cycle-dependent and -independent functions. Biochem Soc Trans 2010, 38: 65–71. 10.1042/BST0380065View ArticlePubMedGoogle Scholar
- Buchakjian MR, Kornbluth S: The engine driving the ship: metabolic steering of cell proliferation and death. Nat Rev Mol Cell Biol 2010, 11: 715–27. 10.1038/nrm2972View ArticlePubMedGoogle Scholar
- Qiao X, Zhang L, Gamper AM, Fujita T, Wan Y: APC/C-Cdh1: from cell cycle to cellular differentiation and genomic integrity. Cell Cycle 2010, 9: 3904–12. 10.4161/cc.9.19.13585PubMed CentralView ArticlePubMedGoogle Scholar
- Arnason TG, Pisclevich MG, Dash MD, Davies GF, Harkness TA: Novel interaction between Apc5p and Rsp5p in an intracellular signaling pathway in Saccharomyces cerevisiae . Eukaryot Cell 2005, 4: 134–146. 10.1128/EC.4.1.134-146.2005PubMed CentralView ArticlePubMedGoogle Scholar
- Harkness TA, Davies GF, Ramaswamy V, Arnason TG: The ubiquitin-dependent targeting pathway in Saccharomyces cerevisiae plays a critical role in multiple chromatin assembly regulatory steps. Genetics 2002, 162: 615–632.PubMed CentralPubMedGoogle Scholar
- Harkness TA, Arnason TG, Legrand C, Pisclevich MG, Davies GF, Turner EL: Contribution of CAF-I to anaphase-promoting-complex-mediated mitotic chromatin assembly in Saccharomyces cerevisiae . Eukaryot Cell 2005, 4: 673–684. 10.1128/EC.4.4.673-684.2005PubMed CentralView ArticlePubMedGoogle Scholar
- Harkness TA: Chromatin assembly from yeast to man: Conserved factors and conserved molecular mechanisms. Curr Genomics 2005, 6: 227–240. 10.2174/1389202054395937View ArticleGoogle Scholar
- Turner EL, Malo ME, Pisclevich MG, Dash MD, Harkness TA: The Anaphase Promoting Complex interacts with multiple histone modifying enzymes to regulate cell cycle progression in yeast. Eukaryot Cell 2010, 9: 1418–1431. 10.1128/EC.00097-10PubMed CentralView ArticlePubMedGoogle Scholar
- Kotani S, Tanaka H, Yasuda H, Todokoro K: Regulation of APC Activity by Phosphorylation and Regulatory Factors. J Cell Biol 1998, 146: 791–800.View ArticleGoogle Scholar
- Rudner AD, Murray AW: Phosphorylation by Cdc28 activates the Cdc20-dependent activity of the anaphase-promoting complex. J Cell Biol 2000, 149: 1377–1390. 10.1083/jcb.149.7.1377PubMed CentralView ArticlePubMedGoogle Scholar
- Harkness TA, Shea KA, Legrand C, Brahmania M, Davies GF: A functional analysis reveals dependence on the anaphase-promoting complex for prolonged life span in yeast. Genetics 2004, 168: 759–774. 10.1534/genetics.104.027771PubMed CentralView ArticlePubMedGoogle Scholar
- Nasmyth K: How do so few control so many? Cell 2005, 120: 739–746. 10.1016/j.cell.2005.03.006View ArticlePubMedGoogle Scholar
- Suijkerbuijk SJ, Kops GJ: Preventing aneuploidy: the contribution of mitotic checkpoint proteins. Biochim Biophys Acta 2008, 1786: 24–31.PubMedGoogle Scholar
- Simonetta M, Manzoni R, Mosca R, Mapelli M, Massimiliano L, Vink M, Novak B, Musacchio A, Ciliberto A: The influence of catalysis on mad2 activation dynamics. PLoS Biol 2009, 7: e10. 10.1371/journal.pbio.1000010View ArticlePubMedGoogle Scholar
- Benhamed M, Bertrand C, Servet C, Zhou DX: Arabidopsis GCN5, HD1, and TAF1/HAF2 interact to regulate histone acetylation required for light-responsive gene expression. Plant Cell 2006, 18: 2893–2903. 10.1105/tpc.106.043489PubMed CentralView ArticlePubMedGoogle Scholar
- Vetting MW, Magnet S, Nieves E, Roderick SL, Blanchard JS: A bacterial acetyltransferase capable of regioselective N-acetylation of antibiotics and histones. Chem Biol 2004, 11: 565–573. 10.1016/j.chembiol.2004.03.017View ArticlePubMedGoogle Scholar
- Landry J, Sutton A, Tafrov ST, Heller RC, Stebbins J, Pillus L, Sternglanz R: The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc Natl Acad Sci USA 2000, 97: 5807–5811. 10.1073/pnas.110148297PubMed CentralView ArticlePubMedGoogle Scholar
- Vogelauer M, Wu J, Suka N, Grunstein M: Global histone acetylation and deacetylation in yeast. Nature 2000, 408: 495–498. 10.1038/35044127View ArticlePubMedGoogle Scholar
- Green SR, Johnson AD: Promoter-dependent roles for the Srb10 cyclin-dependent kinase and the Hda1 deacetylase in Tup1-mediated repression in Saccharomyces cerevisiae . Mol Biol Cell 2004, 15: 4191–4202. 10.1091/mbc.E04-05-0412PubMed CentralView ArticlePubMedGoogle Scholar
- Lee TI, Causton HC, Holstege FC, Shen WC, Hannett N, Jennings EG, Winston F, Green MR, Young RA: Redundant roles for the TFIID and SAGA complexes in global transcription. Nature 2000, 405: 701–704. 10.1038/35015104View ArticlePubMedGoogle Scholar
- Koç A, Wheeler LJ, Mathews CK, Merrill GF: Replication-independent MCB gene induction and deoxyribonucleotide accumulation at G1/S in Saccharomyces cerevisiae . J Biol Chem 2003, 278: 9345–9352. 10.1074/jbc.M213013200View ArticlePubMedGoogle Scholar
- Imoberdorf RM, Topalidou I, Strubin M: A role for gcn5-mediated global histone acetylation in transcriptional regulation. Mol Cell Biol 2006, 26: 1610–1616. 10.1128/MCB.26.5.1610-1616.2006PubMed CentralView ArticlePubMedGoogle Scholar
- Larschan E, Winston F: The Saccharomyces cerevisiae Srb8-Srb11 complex functions with the SAGA complex during Gal4-activated transcription. Mol Cell Biol 2005, 25: 114–123. 10.1128/MCB.25.1.114-123.2005PubMed CentralView ArticlePubMedGoogle Scholar
- Papamichos-Chronakis M, Petrakis T, Ktistaki E, Topalidou I, Tzamarias D: Cti6, a PHD domain protein, bridges the Cyc8-Tup1 corepressor and the SAGA coactivator to overcome repression at GAL1. Mol Cell 2002, 9: 1297–1305. 10.1016/S1097-2765(02)00545-2View ArticlePubMedGoogle Scholar
- Proft M, Struhl K: Hog1 kinase converts the Sko1-Cyc8-Tup1 repressor complex into an activator that recruits SAGA and SWI/SNF in response to osmotic stress. Mol Cell 2002, 9: 1307–1317. 10.1016/S1097-2765(02)00557-9View ArticlePubMedGoogle Scholar
- DeSimone AM, Laney JD: Corepressor-directed preacetylation of histone H3 in promoter chromatin primes rapid transcriptional switching of cell-type-specific genes in yeast. Mol Cell Biol 2010, 30: 3342–3356. 10.1128/MCB.01450-09PubMed CentralView ArticlePubMedGoogle Scholar
- Lin YY, Qi Y, Lu JY, Pan X, Yuan DS, Zhao Y, Bader JS, Boeke JD: A comprehensive synthetic genetic interaction network governing yeast histone acetylation and deacetylation. Genes Dev 2008, 22: 2062–2074. 10.1101/gad.1679508PubMed CentralView ArticlePubMedGoogle Scholar
- Costanzo M, Baryshnikova A, Bellay J, Kim Y, Spear ED, Sevier CS, Ding H, Koh JL, Toufighi K, Mostafavi S, Prinz J, St Onge RP, VanderSluis B, Makhnevych T, Vizeacoumar FJ, Alizadeh S, Bahr S, Brost RL, Chen Y, Cokol M, Deshpande R, Li Z, Lin ZY, Liang W, Marback M, Paw J, San Luis BJ, Shuteriqi E, Tong AH, van Dyk N, Wallace IM, Whitney JA, Weirauch MT, Zhong G, Zhu H, Houry WA, Brudno M, Ragibizadeh S, Papp B, Pál C, Roth FP, Giaever G, Nislow C, Troyanskaya OG, Bussey H, Bader GD, Gingras AC, Morris QD, Kim PM, Kaiser CA, Myers CL, Andrews BJ, Boone C: The genetic landscape of a cell. Science 2010, 327: 425–431. 10.1126/science.1180823View ArticlePubMedGoogle Scholar
- Edmondson DG, Smith MM, Roth SY: Repression domain of the yeast global repressor Tup1 interacts directly with histones H3 and H4. Genes Dev 1996, 10: 1247–1259. 10.1101/gad.10.10.1247View ArticlePubMedGoogle Scholar
- Fillingham J, Recht J, Silva AC, Suter B, Emili A, Stagljar I, Krogan NJ, Allis CD, Keogh MC, Greenblatt JF: Chaperone control of the activity and specificity of the histone H3 acetyltransferase Rtt109. Mol Cell Biol 2008, 28: 4342–4353. 10.1128/MCB.00182-08PubMed CentralView ArticlePubMedGoogle Scholar
- Vernarecci S, Ornaghi P, Bâgu A, Cundari E, Ballario P, Filetici P: Gcn5p plays an important role in centromere kinetochore function in budding yeast. Mol Cell Biol 2008, 28: 988–996. 10.1128/MCB.01366-07PubMed CentralView ArticlePubMedGoogle Scholar
- Kanta H, Laprade L, Almutairi A, Pinto I: Suppressor analysis of a histone defect identifies a new function for the hda1 complex in chromosome segregation. Genetics 2006, 173: 435–450. 10.1534/genetics.105.050559PubMed CentralView ArticlePubMedGoogle Scholar
- Rundlett SE, Carmen AA, Suka N, Turner BM, Grunstein M: Transcriptional repression by UME6 involves decaetylation of lysine 5 of histone H4 by RPD3. Nature 1998, 392: 831–835. 10.1038/33952View ArticlePubMedGoogle Scholar
- Suka N, Nakashima E, Shinmyozu K, Hidaka M, Jingami H: The WD40-repeat protein Pwp1p associates with 25S ribosomal chromatin in a histone H4 tail-dependent manner. Nucleic Acid Res 2006, 34: 3555–3567. 10.1093/nar/gkl487PubMed CentralView ArticlePubMedGoogle Scholar
- Schnekenburger M, Peng L, Puga A: HDAC1 bound to the Cyp1a1 promoter blocks histone acetylation associated with Ah receptor-mediated trans-activation. Biochim Biophys Acta 2007, 1769: 569–578.PubMed CentralView ArticlePubMedGoogle Scholar
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