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Mol Cell Biol, February 1998, p. 1049-1054, Vol. 18, No. 2
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Mutations in Chromatin Components Suppress a Defect
of Gcn5 Protein in Saccharomyces cerevisiae
José
Pérez-Martín1 and
Alexander D.
Johnson1,2,*
Department of Microbiology and
Immunology1 and
Department of
Biochemistry and Biophysics,2 University of
California, San Francisco, California 94143-0414
Received 15 September 1997/Returned for modification 22 October
1997/Accepted 18 November 1997
 |
ABSTRACT |
The yeast GCN5 gene encodes the catalytic subunit of a
nuclear histone acetyltransferase and is part of a
high-molecular-weight complex involved in transcriptional regulation.
In this paper we show that full activation of the HO
promoter in vivo requires the Gcn5 protein and that defects in this
protein can be suppressed by deletion of the RPD3 gene,
which encodes a histone deacetylase. These results suggest an interplay
between acetylation and deacetylation of histones in the regulation of
the HO gene. We also show that mutations in either the H4
or the H3 histone gene, as well as mutations in the SIN1
gene, which encodes an HMG1-like protein, strongly suppress the defects
produced by the gcn5 mutant. These results suggest a
hierarchy of action in the process of chromatin remodeling.
| |
INTRODUCTION |
Nuclear processes, including
transcription, require that enzymes gain access to the eukaryotic DNA
template despite the fact that it is complexed with histone and
nonhistone proteins to form chromatin. Genetic studies with
Saccharomyces cerevisiae have identified two groups of genes
that appear to link transcriptional regulation to chromatin structure
(40). The first group encodes components of the SWI/SNF
complex, which has been proposed to antagonize the repressive effects
of chromatin on transcription (24). SWI/SNF genes
were identified in genetic screens for mutants defective in the
expression of various genes, including the HO and
SUC2 genes (2, 18, 22, 32). The second group of
genes includes various SPT and SIN genes, which
were defined as suppressors of various types of transcriptional defects
(40). The sin2-1 mutation was found to lie in the
HHT1 gene, which encodes histone H3. Five additional
different point mutations, two in histone H3 and three in histone H4,
also displayed a Sin
/Spt phenotype
(12, 25). These mutations affect residues that are believed
either to contact DNA or to be involved in histone-histone contacts
within the histone octamer (39). The SIN1 gene
was found to encode a protein with similarities to mammalian HMG1, a
structural component of chromatin (11). Although the precise role of yeast SIN1 is not known, the similarity of sin1 and
sin2-1 mutant phenotypes has led to the inference that these
two genes have related physiological functions.
Recently, a group of genes involved in acetylation and deacetylation of
histones has been recognized. Histone acetylation has long been
correlated with the modulation of gene activity (37).
Acetylation of lysines in histone amino-terminal tail domains reduces
the positive charge, thereby weakening histone-DNA interactions,
destabilizing higher-order structure, and rendering nucleosomal DNA
more accessible to transcriptional factors (4, 14). Yeast
Gcn5 was originally identified as a regulatory factor required for
function of the yeast activator Gcn4 (5), and recently it
has been shown that Gcn5 is a histone acetyltransferase (3, 13,
28) that is part of at least two high-molecular-weight complexes
called ADA (8) and SAGA (7). The recruitment of these complexes to DNA is thought to direct the local destabilization of nucleosomes, producing more efficient transcriptional activation on
a promoter. Aside from transcriptional regulators that function as
histone acetyltransferases, there are also regulators that deacetylate
the histones (29, 36). These deacetylases comprise part of a
transcriptional repression pathway conserved from yeast to
vertebrates and provide a molecular mechanism whereby
transcription can be continually controlled (19, 38).
In this paper we show that the expression of the HO gene is
affected by defects in histone acetylation and deacetylation. Previous
work has shown that the SWI/SNF complex and structural components of
chromatin also affect HO expression (11, 12, 16,
22). We present an analysis of single and double mutations in the
genes encoding several of these components, and the results suggest a
hierarchy in the chromatin remodeling process.
| |
MATERIALS AND METHODS |
Strains and media.
All strains of S. cerevisiae
used in this study are described in Table
1. Complete medium (yeast
extract-peptone-dextrose [YEPD]) and minimal medium supplemented with
the required amino acids were used for yeast growth and transformations
(26). Histidine limitation was accomplished by supplementing
minimal media with 10 mM 3-amino-1,2,4-triazole (3-AT) (5).
Strain constructions.
Single mutants were obtained either by
gene disruptions performed by using the one-step replacement method
(27) or by gene conversions carried out by a two-step gene
replacement procedure (31). Double and triple mutants were
obtained by crossing single mutants of opposite mating types and
selecting segregants carrying the desired mutations.
A strain carrying a
swi5::LEU2 null allele was
generated as described in reference
34. The
gcn5::hisG strain was generated
as described in
reference
15. The
HO-lacZ fusion allele
is described
in reference
30. The histone mutations
were introduced in the
chromosome by a two-step replacement procedure
(
31) using integrating
plasmids marked with the
URA3 gene (obtained from R. K. Tabtiang
and I. Herskowitz); as these mutations are partially dominant,
it is possible
to observe their effects, even in the presence
of another histone gene
copy (
12). The
rpd3
::LEU2 strain was
generated by transforming yeast with pDM176 digested with
BamHI.
This plasmid carries the
RPD3 locus with a
replacement of the
entire
RPD3 open reading frame (ORF) with
the
LEU2 gene (
15a).
Correct integration was
tested by PCR analysis using oligonucleotides
flanking the
RPD3 locus. The
sin1::TRP1 deletion
strains were
generated by transforming yeast with
pUC-SIN1::TRP linearized
with
EcoRI-
SphI. This plasmid carries a replacement of
the
SIN1 ORF with the
TRP1 gene (
11).
Correct integration was tested
by PCR analysis using oligonucleotides
flanking the
SIN1 locus.
RNA analysis.
Strains were grown to mid-log phase in YEPD
medium. Total-yeast RNA was isolated and fractionated on formaldehyde
gels, transferred to nylon membranes (Genescreen; DuPont), and
hybridized with random-primed 32P-labeled fragments. The
DNA probes used were obtained as PCR fragments by amplification of the
desired ORF with specific primers (MapPairs; Research Genetics Inc.),
with the exception of the HO probe, which was obtained as a
2.6-kb HindIII fragment from the plasmid pGAL-HO
(9).
Other methods.
Yeast cells were transformed by the LiOAc
method (6). 
-Galactosidase assays were performed as
described elsewhere (26).
| |
RESULTS |
The Gcn5 protein is required for HO expression.
HO gene expression is dependent on SWI5. This
gene encodes a zinc finger DNA-binding protein which binds
specifically, along with the PHO2 protein, to the upstream region of
the HO promoter (1, 34). Genetic studies have
described a series of extragenic suppressor mutations that permit
expression of HO in the absence of the SWI5 gene
product (17, 33). Two of the genes identified in this
screen, RPD3 and SIN3, encode, respectively, a
histone deacetylase and a protein tightly associated with it (10,
29, 35). The fact that mutations in the gene pair
SIN3/RPD3 are able to suppress the absence of the Swi5
protein suggests that one of the roles of the Swi5-Pho2 heterodimer is
the recruitment, either directly or indirectly, of a histone
acetyltransferase activity. A likely candidate is the GCN5
gene, which encodes a protein with histone acetyltransferase activity
(13). To test this idea, we examined the levels of
HO mRNA produced in wild-type and isogenic gcn5
mutant strains (obtained by disruption of the GCN5 gene; see
Materials and Methods). We found that a gcn5 mutant strain
produced significantly less HO mRNA (Fig.
1A). By contrast, the absence of the Gcn5
protein did not impair the normal levels of PHO2 and
SWI5 mRNA.
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FIG. 1.
Gcn5 is required for HO expression. (A)
Effects of gcn5 disruption on the mRNA levels of the
HO, PHO2, and SWI5 genes. Total RNA
was extracted from FY120 (GCN5) and JJY54
(gcn5::hisG) grown in YEPD medium to mid-log
phase. ACT1 mRNA was used as a control. (B) Genetic
relationships between SWI5 and GCN5.
-Galactosidase activity was measured in strains carrying an
HO-lacZ reporter gene integrated in the chromosome at the
HO locus. The strains used were JJY12 (wild type [wt]),
JJY28 (gcn5::hisG), JJY13
(swi5::hisG), and JJY60
(gcn5::hisG swi5::hisG). Values are
averages of three independent measurements with less than 10%
deviation.
|
|
In principle,
SWI5 and
GCN5 gene products could
act in the same pathway or through different pathways to activate
HO expression.
If two genes act in the same pathway, then
the phenotype of the
double mutant should be the same as that of one of
the single
mutants. On the other hand, if two genes act through
different
pathways, then the phenotype of the double mutant should be
more
severe than that of either single mutant. To distinguish between
these two possibilities, we measured the
-galactosidase activity
produced by a chromosomal
HO-lacZ gene fusion in a
swi5 gcn5 double
mutant and compared it to those in the
single mutants (Fig.
1B).
HO-lacZ expression in the
gcn5 and
swi5 mutants was reduced 50-
and
200-fold, respectively. In the double mutant,
HO-lacZ
expression
was reduced 200-fold. The
-galactosidase values of the
swi5 mutant
are so low (0.5 Miller units) that we cannot
make a conclusive
argument about the relationship of
SWI5
and
GCN5. However, since
both defects are suppressed by the
same mutations (i.e., by
rpd3,
sin1, and
sin2 mutations; see below) and since the levels of mRNA
for
SWI5 and
PHO2 genes are not affected by
gcn5 mutations (Fig.
1A), these facts support the idea that
SWI5 and
GCN5 act in the
same pathway to
stimulate
HO expression.
Deletion of the RPD3 gene suppresses the
gcn5 mutation.
The results described above are
compatible with the idea that histone acetylation is required for
maximal HO transcriptional activation. According to this
hypothesis, a mutation in a gene encoding a deacetylase should be able
to suppress a gcn5 mutation. A likely candidate is the
RPD3 gene, since mutations in this gene suppress the Swi5
requirement in the HO gene (35). We therefore measured HO-lacZ activity in single and double mutants
carrying null alleles of the GCN5 and RPD3 genes.
The results (Fig. 2) show that a deletion
of the deacetylase gene RPD3 alleviates the requirement for
the histone acetyltransferase gene GCN5 in HO gene expression. The level of suppression of a gcn5 mutation
by the deletion of RPD3 is similar to that observed in the
case of swi5 mutations (35) and is also similar
to the suppression observed in a triple swi5 gcn5 rpd3
mutant, again supporting the view that SWI5 and
GCN5 function in the same pathway.
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FIG. 2.
A deletion of the RPD3 gene partially
suppresses the defects caused by a disruption of the GCN5
gene. Cultures of JJY1 (wild type [wt]), JJY64
(rpd3::LEU2), JJY28
(gcn5::hisG), and JJY65
(rpd3::LEU2 gcn5::hisG) cells
(approximately 5 × 106/ml) were spotted in 10-fold
serial dilutions on medium lacking histidine (SD-HIS) and on medium
lacking histidine and containing 10 mM 3-AT. Plates were incubated at
30°C for 3 days. The same cultures were used to measure
-galactosidase activity (in Miller units). Values are averages of
three independent measurements with less than 10% deviation.
|
|
One of the defects originally observed in
gcn5 mutant
strains was their inability to grow in media imposing amino acid
limitation
(
20). Thus, a strain carrying a deletion of the
GCN5 gene is
defective in growth in media containing 3-AT, a
condition that
mimics histidine starvation (
5). To address
whether a deletion
in the
RPD3 gene suppresses other defects
in
gcn5 strains, we
also tested the ability of the
RPD3 deletion to allow growth of
a
gcn5 strain in
the presence of 3-AT. As shown in Fig.
2, the
gcn5 strain
exhibited a growth defect under such conditions compared
with an
isogenic wild-type strain. Deletion of the
RPD3 gene indeed
alleviates this defect, allowing growth of the
gcn5 strain
under
these conditions.
Disruption of SIN1, a gene encoding an HMG1-like
protein, also suppresses gcn5 defects.
In addition to
sin3 and rpd3 mutations, defects in other genes
are well-known suppressors of transcriptional deficiencies in
HO. One of these genes is SIN1. This gene encodes
a protein with similarities to the mammalian HMG1 protein, and it is
believed to be a component of chromatin (11). We have
monitored both HO-lacZ expression and the ability to grow in
the presence of 3-AT of a double mutant defective in both
GCN5 and SIN1. The results shown in Fig.
3 indicate that the absence of Sin1
protein relieves the requirement of Gcn5 both for HO
expression and for growth on 3-AT.
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FIG. 3.
Deletion of the SIN1 gene alleviates the
defects associated with disruption of the GCN5 gene.
Cultures of JJY12 (wild type [wt]), JJY36
(sin1::TRP1), JJY28
(gcn5::hisG), and JJY45
(sin1::TRP1 gcn5::hisG) cells
(approximately 5 × 106/ml) were spotted in 10-fold
serial dilutions on medium lacking histidine (SD-HIS) and on medium
lacking histidine and containing 10 mM 3-AT. Plates were incubated at
30°C for 3 days. The same cultures were used to measure
-galactosidase activity (in Miller units). Values are averages of
three independent measurements with less than 10% deviation.
|
|
Histone mutations also suppress gcn5 defects.
An
explanation for the results obtained with the sin1 mutant is
that the suppression we observed is caused by a defect in chromatin
structure, such that this defective chromatin bypasses the requirement
for histone acetylation. If this is the case, then other mutations
which produce defective chromatin might also be expected to suppress
the gcn5 defects. Certain amino acid changes (sin
mutations) in either histone H3 or histone H4 alleviate the same set of
transcriptional defects as does the sin1 mutation (12,
23). These sin mutations lie in the histone fold
domain of histones H3 and H4, and they are in close proximity to one another on the surface of the histone octamer. It has been proposed that residues altered by these mutations may define a functional domain
(the SIN domain) that behaves formally as a negative regulator of
transcription (12).
To address if defective histones also suppress
gcn5
mutations, the following histone mutant alleles were tested for their
ability to suppress a deletion of the
GCN5 gene:
sin2-1 (R116H
in
HHT1),
hhf2-7 (R45C
in
HHF4),
hhf2-8 (V43I in
HHF4), and
hhf2-13 (R45H in
HHF4). In spite of the fact that
the targets for GCN5
protein are the histone tails, mutations in the
histone fold are
able to efficiently suppress the defects caused by the
absence
of the
GCN5 gene product (Fig.
4A).
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FIG. 4.
Histone sin mutations suppress
gcn5 defects. (A) Cultures of JJY12 (wild type [wt]),
JJY28 (gcn5::hisG), JJY41 (hhf2-7
gcn5::hisG), JJY42 (hhf2-8
gcn5::hisG), JJY43 (hhf2-13
gcn5::hisG), and JJY44 (sin2-1
gcn5::hisG) cells (approximately 5 × 106/ml) were spotted in 10-fold serial dilutions on medium
lacking histidine (SD-HIS) and on medium lacking histidine and
containing 10 mM 3-AT. Plates were incubated at 30°C for 3 days. The
same cultures were used to measure -galactosidase activity (in
Miller units). Values are averages of three independent measurements
with less than 10% deviation. (B) Effects of rpd3 deletion
on the suppression of gcn5 defects by histone sin
mutations and sin1 mutations. The strains used were JJY12,
JJY28, and JJY41 through JJY44 (all as described for panel A), as well
as JJY65 (rpd3::LEU2 gcn5::hisG),
JJY72 (hhf2-7 rpd3::LEU2 gcn5::hisG),
JJY73 (hhf2-8 rpd3::LEU2 gcn5::hisG),
JJY74 (hhf2-13 rpd3::LEU2
gcn5::hisG), and JJY75 (sin2-1
rpd3::LEU2 gcn5::hisG). Values are averages
of three independent measurements with less than 10% deviation.
|
|
We also determined the effects of combining a deletion of the
RPD3 gene with the histone
sin mutations. Levels
of
HO-lacZ activity were determined in single and double
mutants, and we
found in the double mutants a strong synergistic
effect; that
is, the activity displayed by the double mutant is higher
than
the sum of the activities displayed by the single mutants (Fig.
4B). The same synergistic effect is also seen in combinations
of
rpd3 and
sin1 mutations (data not shown).
| |
DISCUSSION |
Regulation of the yeast HO gene is complex,
and many genes that regulate HO have been identified
(16). These include genes encoding the SWI/SNF complex
(22, 32); SIN1, which encodes an HMG1-like
protein (11); SIN2, which encodes histone H3;
HHF4, which encodes histone H4 (12); and
SIN3, which, along with RPD3, is involved in the
deacetylation of histones (35). In this paper, we show a
requirement for the GCN5 gene, which encodes a histone acetyltransferase (3), for optimal transcription of the
HO gene.
The identification of histone acetyltransferases and histone
deacetylases as transcriptional regulators provides molecular mechanisms whereby transcription might be turned up or down
(38), but so far no such interplay between acetylase and
deacetylase activities at a single gene has been reported. The
suppression of the gcn5 defects by deletion of one of the
genes encoding a deacetylase activity provides clear support for such
interplay at the HO promoter. The suppression we observed is
only partial, suggesting a functional redundancy in the deacetylase
activity. Another protein with deacetylase activity is encoded by the
gene HDA1, and three additional ORFs with high levels of
homology with RPD3 and HDA1 have also been
described (29). However, we observed that deletion of
HDA1 or of one of these additional ORFs (HOS1) does not suppress the GCN5 requirement in HO
expression (data not shown). Another explanation for the fact that
suppression is only partial is that the rpd3 deletion may
destabilize additional proteins with which it is complexed
(7), and these additional proteins may contribute to the
activation of HO.
The pattern of genetic interactions described in this work suggests a
hierarchy of gene function that pertains to chromatin components,
histone acetylation, and the SWI/SNF complex. Loss of Swi5 (the major
activator protein for the HO gene [16]) can be partially suppressed by sin1, sin2 (histone
H3), sin3, and rpd3 mutations (33,
35). Loss of GCN5 (a histone acetyltransferase, also required for
HO transcription) can be suppressed by these same mutations
(Fig. 2, 3, and 4A). However, while defects in the SWI/SNF complex can
be suppressed by sin1 (which is thought to be a target of
the SWI/SNF complex [21] and sin2 mutations (11, 12), they cannot be suppressed efficiently by
sin3 or rpd3 mutations (33, 35). These
results indicate that histone acetylation at the HO promoter
functions upstream of the SWI/SNF complex. Consistent with this view is
the strong synergy seen between rpd3 mutations (which affect
the acetylation of histone tails) and sin1 and
sin2 mutations (which circumvent the need for the SWI/SNF
complex) (Fig. 4B). One hypothesis consistent with this genetic
hierarchy is that, at the HO promoter, histone acetylation
precedes and enables the action of the SWI/SNF complex. A similar view
has recently been developed independently by Pollard and Peterson
(24a).
| |
ACKNOWLEDGMENTS |
We thank D. Moazed, R. K. Tabtiang, and R. Candau
for providing indispensable strains and plasmids throughout the course
of this work. D. Moazed is also acknowledged for critical reading of
the manuscript.
This work was supported by an NIH grant to A.D.J. and by an EMBO
long-term postdoctoral fellowship to J.P.-M.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Microbiology and Immunology, University of California, 513 Parnassus Ave., San Francisco, CA 94143-0859. Phone: (415) 476-8783. Fax: (415)
476-0939. E-mail: ajohnson{at}socrates.ucsf.edu.
| |
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Mol Cell Biol, February 1998, p. 1049-1054, Vol. 18, No. 2
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
