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A General Requirement for the Sin3-Rpd3 Histone Deacetylase Complex in Regulating Silencing in Saccharomyces cerevisiae
Zu-Wen Sun1,a and Michael Hampseyaa Department of Biochemistry, Division of Nucleic Acids Enzymology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854
Corresponding author: Michael Hampsey, Department of Biochemistry, UMDNJRobert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854. E-mail:hampsemi@umdnj.edu
Communicating editor: F. WINSTON
| ABSTRACT |
|---|
The Sin3-Rpd3 histone deacetylase complex, conserved between human and yeast, represses transcription when targeted by promoter-specific transcription factors. SIN3 and RPD3 also affect transcriptional silencing at the HM mating loci and at telomeres in yeast. Interestingly, however, deletion of the SIN3 and RPD3 genes enhances silencing, implying that the Sin3-Rpd3 complex functions to counteract, rather than to establish or maintain, silencing. Here we demonstrate that Sin3, Rpd3, and Sap30, a novel component of the Sin3-Rpd3 complex, affect silencing not only at the HMR and telomeric loci, but also at the rDNA locus. The effects on silencing at all three loci are dependent upon the histone deacetylase activity of Rpd3. Enhanced silencing associated with sin3
, rpd3
, and sap30
is differentially dependent upon Sir2 and Sir4 at the telomeric and rDNA loci and is also dependent upon the ubiquitin-conjugating enzyme Rad6 (Ubc2). We also show that the Cac3 subunit of the CAF-I chromatin assembly factor and Sin3-Rpd3 exert antagonistic effects on silencing. Strikingly, deletion of GCN5, which encodes a histone acetyltransferase, enhances silencing in a manner similar to deletion of RPD3. A model that integrates the effects of rpd3
, gcn5
, and cac3
on silencing is proposed.
EPIGENETIC effects are heritable, but reversible, changes in gene expression due to alterations in chromatin structure or DNA methylation (reviewed in ![]()
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In addition to silencing at the cryptic HM mating loci, silencing in yeast has been described for reporter genes integrated proximal to telomeres (telomere position effect; ![]()
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The combination of yeast genetics and biochemistry has led to the discovery of many factors that affect silencing. These include the silent information regulatory (SIR) proteins, the repressor-activator protein Rap1, and the core histones H3 and H4 (![]()
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Other proteins also play important roles in silencing. Rad6 (Ubc2) is an E2 ubiquitin-conjugating enzyme involved in many cellular processes, including DNA repair, UV-induced mutagenesis, N-end rule protein degradation, sporulation (reviewed in ![]()
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The chromatin assembly factor I (CAF-I) also affects silencing. Yeast CAF-I is composed of three subunits encoded by the CAC1, CAC2, and CAC3 genes (![]()
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Silent DNA is packaged into hypoacetylated nucleosomes that exhibit a pattern of histone acetylation reminiscent of metazoan heterochromatin (![]()
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Mammalian and yeast Sin3 and Rpd3 proteins exist in large multisubunit complexes, estimated to be >2 MD in the case of the yeast Sin3-Rpd3 complex (![]()
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, rpd3
, and sap30
mutants; furthermore, Sap30 coimmunoprecipitates with Rpd3 (![]()
It is presently unknown how many proteins affect silencing in yeast. Furthermore, the mechanisms by which these factors mediate silencing are unknown. In this study we have examined the role of the Sin3-Rpd3 complex in silencing at the telomeric, HMR, and rDNA loci. Our results demonstrate that the Sin3-Rpd3 complex plays a general role in silencing. Surprisingly, loss of the Gcn5 histone acetyltransferase exerts the same effect on silencing as loss of the Rpd3 histone deacetylase, yet Rpd3 and Gcn5 exert opposite effects on promoter-dependent, position-independent transcription. We propose a model to account for these results.
| MATERIALS AND METHODS |
|---|
Yeast strains and media:
The yeast strains used in this study are listed in Table 1. The YMH strains were derived from strain UCC506 (![]()
sir2 (![]()
![]()
![]()
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![]()
|
Plasmids:
Plasmids used in this study are listed in Table 2. Vectors pRS303 and pRS306 (![]()
![]()
::URA3
-disruption construct, pM1061, was generated by transferring the SalI-SstI fragment of M1436 (rpd3
::LEU2) to the same sites of pRS306. YEplac112-RPD3 includes the entire RPD3 open reading frame inserted between the ADH1 promoter and CYC8 terminator in YEplac112. YEplac112-rpd3 (H188A) is identical to YEplac112-RPD3, except that it encodes a form of Rpd3 lacking detectable histone deacetylase activity in vitro (![]()
::LEU2
-disruption construct, pM1177, was constructed by ligation of the PCR-amplified PstI-SalI C-terminal fragment of SAP30 (nucleotides 3851370) and the BamHI-SstI fragment (nucleotides 1590) from pM1176 into PstI-SalI and BamHI-SstI sites of YIplac128, respectively. The sap30
::TRP1 construct, pM1183, was generated by transferring the SphI-SstI fragment of pM1177 (sap30
::LEU2) to the same sites of YIplac204.
|
Assays for telomeric, HMR, and rDNA silencing:
Telomeric silencing was scored as described previously (![]()
The rpd3
rad6
and rpd3
gcn5
double mutants display synthetic slow-growth phenotypes (data not shown). Therefore, silencing at the telomeric URA3 gene (URA3-TEL-V-R) in these strains was scored by measuring cell viability on 5-FOA medium as described previously (![]()
| RESULTS |
|---|
Deletion of SAP30 enhances silencing at the HMR locus:
To determine whether the Sap30 component of the Sin3-Rpd3 complex plays a general role in silencing, we asked if deletion of SAP30 affects silencing at the HMR locus. Strain yLP19, which contains the ADE2 gene integrated at the hmr
A locus (hmr
A::ADE2; ![]()
(YMH348), sin3
(YMH345), and sap30
(YMH349) strains, were used in this analysis. Expression of ADE2 allows cell growth on medium lacking adenine (-Ade) and results in a white colony phenotype, whereas enhanced silencing impairs cell growth on -Ade medium and confers a pink or red colony phenotype due to accumulation of a red pigment. Tenfold serial dilutions of each strain were spotted onto -Ade and synthetic complete media (+Ade) and incubated at 30° for 3 days. The sap30
deletion clearly impaired cell growth on -Ade medium, albeit to a lesser extent than either the rpd3
or sin3
deletions (Figure 1A). The sap30
mutant, similar to the rpd3
and sin3
mutants, also formed pink colonies on YPD medium, compared to white colonies for the wild-type strain (data not shown). We conclude that SAP30 counteracts HMR silencing in a manner similar to RPD3 and SIN3.
|
The Sin3-Rpd3 complex affects rDNA silencing:
To determine whether the Sin3-Rpd3 complex plays a general role in silencing, we examined the effects of sin3
, rpd3
, and sap30
deletions on rDNA silencing. Strain CFY559 and isogenic sin3
(YMH333), rpd3
(YMH335), and sap30
(YMH337) deletion mutants were used in this study. CFY559 is an ade2 can1 mutant carrying an ADE2-CAN1 double marker integrated at the rDNA array (![]()
and rpd3
mutants, and a 102- to 103-fold decrease for the sap30
mutant (Figure 1B). The diminished ADE2 expression associated with the rpd3
, sin3
, and sap30
mutations cannot be attributed to loss of the ADE2-CAN1 marker by recombination between the rDNA repeats because these mutants exhibited a uniform pink colony phenotype rather than the red phenotype associated with deletion of the ADE2-CAN1 marker by recombination. Furthermore, transformation of pink rpd3
mutants with plasmid-borne RPD3 rescued the white colony phenotype, an effect that would not occur if the ADE2-CAN1 were deleted (data not shown). Also, the rpd3
, sin3
, and sap30
mutations do not cause an Ade- phenotype when ADE2 is expressed from its normal chromosomal locus (Figure 1C), demonstrating that the Ade- phenotypes associated with these mutations are specific for ADE2 expression from the rDNA locus. Taken together, these results establish that the Sin3-Rpd3 complex also affects silencing at the rDNA locus.
Enhanced silencing associated with rpd3
is SIR dependent:
To determine if the enhanced rDNA silencing associated with loss of components of the Sin3-Rpd3 complex is SIR protein dependent, the SIR2 and SIR4 genes were individually deleted in wild-type (CFY559) and isogenic rpd3
strains containing ADE2-CAN1 integrated at the rDNA array. Silencing at the rDNA locus was again scored by the efficiency of colony formation on -Ade medium and by colony color. Results are shown in Figure 2A. Whereas the rpd3
mutation dramatically increased silencing, the rpd3
sir2
double mutation restored growth to ~83% of the wild-type strain (cf. rows 13). In addition, the rpd3
sir2
mutant exhibited a white colony phenotype, compared to the pink phenotype of the rpd3
single mutant, and this phenotype can be rescued by plasmid-borne RPD3 (data not shown). However, comparison of the rpd3
sir2
double mutant with the sir2
single mutant revealed increased silencing associated with rpd3
in the sir2
background (cf. rows 3 and 5). These results demonstrate that enhanced silencing associated with rpd3
at the rDNA array is SIR2 dependent, but that sir2
is not completely epistatic to rpd3
.
|
The sir4
deletion, however, did not counteract the increase in silencing associated with rpd3
(Figure 2A; cf. rows 2 and 4). Also, the rpd3
single mutant and rpd3
sir4
double mutants displayed comparable pink colony phenotypes (data not shown). Consistent with previous results (![]()
![]()
deletion is Sir2 dependent, but Sir4 independent.
In contrast to the requirements for silencing at the rDNA array, both SIR2 and SIR4 are essential for silencing at the telomeric and HM loci (reviewed in ![]()
![]()
, sir2
, and sir4
derivatives, were used in these experiments. The levels of URA3 silencing were monitored by cell growth on medium containing 5-FOA, which is toxic to cells expressing URA3 (![]()
mutant grew well (Figure 2B; cf. rows 1 and 2). However, no 5-FOA-resistant colonies were observed for the rpd3
sir2
and rpd3
sir4
double mutants or for the sir2
and sir4
single mutants (Figure 2B, rows 36), indicating that silencing of the telomeric URA3 gene was disrupted in these strains. We also did the reciprocal assay, scoring growth of the same strains on -Ura medium to determine whether rpd3
might increase TEL silencing in the sir
background to an extent that might not be apparent in the FOA assay. No significant growth difference between the rpd3
sir2
or rpd3
sir4
double mutants and the sir2
or sir4
single mutants was observed (Figure 2C). [Growth of the double mutants is slightly impaired relative to the single mutants, but this difference can be accounted for by the weak slow-growth phenotype associated with rpd3
, which is reflected in the +Ura control (Figure 2C)]. Thus, in contrast to the SIR4 independence of rDNA silencing, both SIR2 and SIR4 are required for the enhanced telomeric silencing associated with rpd3
.
The Rpd3 effect on silencing is dependent upon histone deacetylase activity:
A histone deacetylase motif, containing evolutionarily invariant histidine residues at positions 150, 151, and 188 (H150, H151, and H188), was recently identified in the Rpd3 protein (![]()
To determine if the enzymatic activity of Rpd3 is required to counteract silencing, plasmid-borne RPD3 and rpd3 (H188A) alleles were introduced into the rpd3
deletion mutants YMH335 and YMH348, which carry the ADE2 marker at rDNA and HMR loci, respectively. Whereas RPD3 rescued the growth defect of strain YMH335 on -Ade medium (Figure 3A, row 3), the rpd3-H188A strain remained Ade- (Figure 3A, row 4). This result demonstrates that RPD3, but not rpd3-H188A, restores the expression of the ADE2 gene integrated at the rDNA locus in the rpd3
mutant. Consistent with this result, strains containing RPD3 or rpd3-H188A formed white and pink colonies, respectively, on YPD medium (data not shown). Similar results were obtained for the strains carrying an ADE2 reporter inserted in the HMR locus (Figure 3B, cf. rows 3 and 4; and data not shown). We also note that plasmid-borne expression of RPD3 results in better growth on selective medium in the rpd3
background than does chromosomally expressed RPD3 for both the RDN1::ADE2 and hmr
::ADE2 strains (Figure 3A and Figure B, rows 3 vs. 1), suggesting that overexpression of RPD3 might weaken silencing. However, overexpression of RPD3, SIN3, or SAP30 in wild-type backgrounds did not weaken silencing at either rDNA or HMR (data not shown).
|
We also examined the requirement for Rpd3 activity in regulating telomeric silencing. In this case strain YMH272 (URA3-TEL-V-R rpd3
) was used as the host and silencing was scored as enhanced growth (diminished URA3 expression) on 5-FOA medium. The host rpd3
strain is 5-FOA-resistant due to enhanced silencing of the URA3 marker (Figure 3C, row 2). This phenotype is rescued by plasmid-borne RPD3, resulting in 5-FOA sensitivity (row 3), but not by the rpd3-H188A plasmid (row 4). Taken together, the results in Figure 3 clearly demonstrate that the enzymatic activity of Rpd3 is required to counteract silencing at telomeric, HMR, and rDNA loci.
Enhanced silencing associated with rpd3
is RAD6 dependent:
Several studies have implicated Rad6-mediated ubiquitination as a regulator of silencing in both S. cerevisiae and Schizosaccharomyces pombe (![]()
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rad6
double mutants (data not shown), we assayed telomeric silencing at URA3-TEL-V-R by measuring viability of isogenic wild-type (UCC506), rpd3
(YMH320), rad6
(YMH405), and rpd3
rad6
(YMH407) strains on 5-FOA medium, rather than by the spotting assays described above. Results are presented in Table 3. As expected, rpd3
enhanced silencing, resulting in a 9000-fold increase in cell viability on 5-FOA medium, whereas rad6
weakened silencing, causing a 17-fold decrease in cell viability. Strikingly, the rpd3
rad6
double deletion further weakened silencing, resulting in a 1.4 x 106-fold decrease in cell viability relative to the rpd3
single mutant. Similar results were observed for sin3
rad6
and sap30
rad6
mutants (data not shown). Thus, the enhanced telomeric silencing associated with loss of the Sin3-Rpd3 complex is Rad6 dependent.
|
Because transcriptional silencing at the rDNA locus is mediated by a novel mechanism that depends on only a single SIR gene, SIR2 (![]()
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exerts an effect on rDNA silencing similar to its effect on telomeric silencing. Deletion mutants comparable to those described above were generated using strain CFY559 (RDN1-ADE2-CAN1) and cell viability was scored on -Ade medium. Results are presented in Table 4. Again, rpd3
(YMH335) enhanced silencing, in this case resulting in a 1500-fold decrease in cell viability. In contrast, rad6
conferred a negligible effect on its own (YMH413), yet fully suppressed the effect of rpd3
in the rpd3
rad6
double mutant (YMH415), resulting in an 1100-fold increase in cell viability. In addition, wild-type (CFY559), rad6
(YMH413), and rpd3
rad6
(YMH415) strains formed white colonies on YPD medium, indicating efficient ADE2 expression, whereas the rpd3
strain was pink (data not shown). Thus, enhanced silencing at the rDNA locus is also Rad6 dependent.
|
Enhanced silencing associated with loss of Sin3-Rpd3 occurs in the absence of CAC3:
Components of the CAF-I complex are required for silencing at the HM and telomeric loci (![]()
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, rpd3
, and sap30
deletions to restore telomeric silencing in a cac3
strain. Silencing at the URA3-TEL-V-R locus was assayed by scoring cell growth on 5-FOA medium, as described above, using an isogenic set of strains with different combinations of cac3
, rpd3
, sin3
, and sap30
deletions. The results are shown in Figure 4. As expected, cac3
weakened silencing, scored as enhanced 5-FOA sensitivity (row 2), whereas sap30
enhanced silencing (row 4). However, the double mutants (row 3) exhibit intermediate phenotypes corresponding to an ~10-fold increase in silencing relative to the wild-type strain (row 1). These effects were the same for deletion of all three components of the Sin3-Rpd3 complex (A, B, and C). Thus, Cac3 and the Rpd3-Sin3 complex exert opposite effects on silencing in a partially offsetting manner. Interestingly, the human counterpart of Cac3, RbAp46, is found as a component of the Sin3-Rpd3 complex. However, there is no evidence that yeast Cac3 is a component of the yeast Sin3-Rpd3 complex.
|
Deletion of GCN5 and RPD3 exerts similar effects on silencing:
Whereas RPD3 encodes a histone deacetylase that is required for transcriptional repression of targeted genes (![]()
![]()
![]()
![]()
![]()
These results suggested that gcn5
, in contrast to rpd3
, might weaken silencing. We tested this possibility by deleting GCN5 in the URA3-TEL-V-R reporter strain UCC506. Surprisingly, gcn5
dramatically enhanced silencing, resulting in a 1500-fold increase in cell viability on FOA medium (Table 3; cf. UCC506 and YMH366). Furthermore, the rpd3
gcn5
double mutation (YMH370) did not increase cell viability beyond the effect of rpd3
alone (YMH320; 9000-fold). A similar effect on silencing was observed at the hmr
A::ADE2 locus, where gcn5
resulted in formation of pink colonies, yet the isogenic wild-type strain remained white (data not shown). These effects are not a consequence of position-independent effects on URA3 and ADE2 expression, because neither rpd3
nor gcn5
mutations confer uracil auxotrophy, FOA resistance, or the pink colony phenotype associated with impaired URA3 or ADE2 expression in an otherwise normal strain. Thus, Gcn5 histone acetyltransferase, like Rpd3 histone deacetylase, counteracts silencing.
| DISCUSSION |
|---|
The Sin3-Rpd3 complex plays a general role in silencing:
A role for Sin3 and Rpd3 in silencing at telomeric and HM cryptic mating loci has been shown previously (![]()
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![]()
Relationship of Rpd3 to Rad6:
Recent studies demonstrated that deletion of RAD6 counteracts silencing at telomeric, HM, and rDNA loci in S. cerevisiae, and at the silent mating loci in S. pombe (![]()
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A striking result presented here is that rad6
is epistatic to the effect of rpd3
on silencing at the telomeric and rDNA loci (Table 3 and Table 4). One possible explanation for this result is that the Rpd3 histone acetyltransferase regulates expression of RAD6, which in turn is required for silencing. However, Western blot analysis showed that Rad6 protein levels are essentially unchanged in isogenic wild-type, rpd3
, and gcn5
strains (data not shown). Therefore, neither Rpd3 nor Gcn5 affects silencing indirectly through RAD6. The more direct effect of Rad6 on silencing is consistent with the possibility that Rad6 affects silencing by ubiquitination of direct effectors of silencing.
Effects of Rpd3 and Gcn5 on silencing:
The Sin3-Rpd3 complex facilitates transcriptional repression as a consequence of targeted recruitment by DNA-binding transcriptional repressors (![]()
![]()
A distinct possibility is that the effect of the Sin3-Rpd3 complex is indirect. For example, Sin3-Rpd3 might repress expression of genes generally required for silencing such that in the absence of Sin3-Rpd3 these genes are derepressed, leading to increased silencing. This scenario seems likely given the general role of Rpd3 in transcriptional repression. Nonetheless, the effect of rpd3
on silencing cannot be accounted for by increased expression of either RAD6 (above) or SIR genes. Overexpression of SIR4 does not enhance silencing, but instead weakens silencing at HMR, telomeric, and rDNA loci (![]()
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A notable and unexpected result presented here is that deletion of GCN5 enhances silencing (Table 3). Accordingly, loss of Gcn5 histone acetyltransferase activity has the same effect on silencing as loss of Rpd3 histone deacetylase activity. This result was surprising because GCN5 and RPD3 exert opposite effects on transcriptional control of genes targeted by both factors. Indeed, defective activation associated with deletion of GCN5 can be suppressed by deletion of RPD3 (![]()
The similar effects of rpd3
and gcn5
on silencing might be an important clue toward understanding how Rpd3 and Gcn5 influence silencing. Even though rpd3
and gcn5
affect the expression of a broad range of genes, rpd3
generally enhances transcription, whereas gcn5
impairs transcription. A stimulatory effect of gcn5
on expression of silencing factors would be opposite to its effect on most genes. This possibility seems especially unlikely if the same factors are also affected by rpd3
. An alternative possibility, described below, is that Rpd3 and Gcn5 affect silencing directly by generating the histone acetylation pattern specific to silent chromatin.
A model for the role of Sin3-Rpd3 in silencing:
A substantial body of evidence indicates that silencing is a consequence of modified chromatin structure (![]()
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Perhaps Rpd3 and Gcn5 affect silencing by catalyzing formation of the histone acetylation pattern resident in silent chromatin. Newly synthesized histone H4 is acetylated at K5 and K12, which are conserved modifications among humans, Drosophila, and Tetrahymena, and this pattern is thought to be important for assembly of H4 onto replicating DNA (![]()
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The following model is proposed to explain the role of Rpd3 in silencing (Figure 5). Accordingly, Rpd3 would play a direct role in silencing by affecting the relative levels of the "inactive" (heterochromatin) and "active" (euchromatin) forms of histone H4. This ratio would affect the efficiency of formation of silent chromatin in much the same way that components of silent chromatin and a transcriptional activator compete to establish either the silent or active state of gene expression at telomeres following the disassembly of silent chromatin during DNA replication. This effect was proposed to account for the random nature of phenotypic switching in variegated gene expression (![]()
![]()
, rpd3
, or sap30
strains, the relative levels of H4 acetylated at K5 and K12 would increase due to loss of histone deacetylase activity. H4 acetylated at K12 is the inactive form, thereby accounting for enhanced silencing associated with loss of Sin3-Rpd3 function. This scenario is dependent upon substrate specificity of Rpd3 for H4 K12. Indeed, rpd3
enhances acetylation of H4 residues K5 and K12 (![]()
|
This model would also account for the enhanced silencing associated with gcn5
(Table 3). Accordingly, the Gcn5 histone acetyltransferase would directly affect silencing by catalyzing acetylation of H4 residues K8 and K16. Consistent with this premise, an H4 K16Q replacement, which simulates acetylated K16, disrupts the interaction between H4 and Sir3 (![]()
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strain, the levels of H4 acetylated at K8 and K16 would decrease, thereby increasing the relative levels of the inactive form of H4 acetylated at K5 and K12. Again, this proposal is consistent with the specificity of Gcn5 for H4 residues K8 and K16 (![]()
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To facilitate inheritance of silencing, CAF-I would ensure that only appropriately acetylated inactive histones (both newly synthesized and recycled from the previous cell cycle) are assembled into silent chromatin (![]()
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![]()
mutants, new nucleosomes must be assembled by an alternative pathway (![]()
![]()
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and either rpd3
, sin3
, or sap30
(Figure 4).
A second function of CAF-I would be to ensure that local Sir2, Sir3, and Sir4 protein concentrations are sufficiently elevated to permit assembly of a strong silencer. This conclusion is based on improved silencing associated with elevated levels of Sir2, Sir3, or Sir4 in cac1
mutants, and on disruption of silencing associated with limiting amounts of Sir2 or Sir3 in an otherwise wild-type background (![]()
would partially weaken the enhanced silencing caused by sin3
, rpd3
, and sap30
. This is consistent with the observation that loss of the Sin3-Rpd3 complex does not bypass the SIR protein requirement for maintaining silencing (Figure 2 and ![]()
A key feature of this model is that the acetylation state of histones affects the efficiency of assembly of silent chromatin. The model does not propose that the acetylation pattern at silent loci would necessarily change upon deletion of RPD3 or GCN5. Indeed, chromatin immunoprecipitation experiments, demonstrating that rpd3
and sin3
alter the acetylation pattern of histone H4 at Ume6-regulated promoters, showed that the H4 acetylation pattern at a telomeric locus is unchanged by rpd3
and sin3
(![]()
| FOOTNOTES |
|---|
1 Present address: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908. ![]()
| ACKNOWLEDGMENTS |
|---|
We are grateful to Jeff Smith, Jef Boeke, Susan Gasser, Ken Robzyk, and Mary Ann Osley for communicating results prior to publication. We also thank Mike Christman, Shelley Esposito, Dan Gottschling, and Lucy Pemberton for yeast strains; Kevin Struhl for rpd3 alleles; and Jim Broach, Leonard Guarente, Kiran Madura, David McNabb, Ines Pinto, Louise Prakash, David Stillman, and Fred Winston for plasmids. We also acknowledge David Gross, Yi Zhang, and Danny Reinberg for fruitful discussions and critical review of the manuscript. Research in M.H.'s laboratory is supported by National Institutes of Health grant GM-39484.
Manuscript received January 22, 1999; Accepted for publication April 16, 1999.
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