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Journal of Bacteriology, August 1999, p. 4755-4760, Vol. 181, No. 16
0021-9193/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Regulation of Gene Expression by Glucose in
Saccharomyces cerevisiae: a Role for ADA2
and ADA3/NGG1
Mei
Wu,1
Laura
Newcomb,2 and
Warren
Heideman2,3,*
Program in Cell and Molecular
Biology,1 Department of Biomolecular
Chemistry,2 and School of
Pharmacy,3 University of Wisconsin, Madison,
Wisconsin 53706
Received 27 April 1999/Accepted 24 May 1999
 |
ABSTRACT |
When Saccharomyces cerevisiae cells are transferred
from poor medium to fresh medium containing glucose, they rapidly
increase the transcription of a large group of genes as they resume
rapid growth and accelerate progress through the cell cycle. Among
those genes induced by glucose is CLN3, encoding a
G1 cyclin that is thought to play a pivotal role in
progression through Start. Deletion of CLN3 delays the
increase in proliferation normally observed in response to glucose
medium. ADA2 and ADA3/NGG1 are necessary for
the rapid induction of CLN3 message levels in response to glucose. Loss of either ADA2 or ADA3/NGG1 also
affects a large number of genes and inhibits the rapid global increase
in transcription that occurs in response to glucose. Surprisingly,
these effects are transitory, and expression of CLN3 and
total poly(A)+ RNA appear normal when ADA2 or
ADA3/NGG1 deletion mutants are examined in log-phase
growth. These results indicate a role for ADA2 and
ADA3/NGG1 in allowing rapid transcriptional responses to
environmental signals. Consistent with the role of the Ada proteins in
positive regulation of CLN3, deletion of RPD3,
encoding a histone deacetylase, prevented the down regulation of
CLN3 mRNA in the absence of glucose.
| |
INTRODUCTION |
When growing cells of the yeast
Saccharomyces cerevisiae deplete the glucose from normal
YEPD growth medium, they decrease both mRNA and protein biosynthesis as
they pass first through the diauxic shift from fermentative to
oxidative growth on ethanol. Eventually the cells deplete a limiting
nutrient and approach stationary phase (36). As this process
proceeds, G1 length steadily increases, allowing the cell
cycle to maintain pace with the steadily decreasing rate of growth in
mass. Cells that fail to return to rapid growth after transfer to rich
medium are at a considerable selective disadvantage. All else being
equal, the more rapidly a cell returns to logarithmic growth in
glucose, the more descendants it will have. The rapid return to growth
after transfer to fresh medium involves a large-scale induction of gene
expression (36). Previous work using labeled poly(dT) probes
suggested that the level of total mRNA in log-phase cells is up to
10-fold higher than in post-log-phase and stationary-phase cultures
(3). More recent work with cDNA microarrays has helped to
clarify this picture by showing that as cells reached glucose
exhaustion at the diauxic shift, the transcription of approximately
17% of the 6,100 genes examined was decreased by glucose exhaustion
(6). Therefore, the transcriptional machinery is able to
recognize a large set of genes that are induced by glucose. Among the
genes turned on in glucose medium are those encoding glycolytic
enzymes, as well as genes promoting protein translation. The emerging
picture therefore suggests that yeast cells make a coordinated response
to glucose that allows them to rapidly increase their rate of growth on
this rich resource. How this process is regulated remains poorly understood.
As cells return to logarithmic growth, the rates of both growth in size
and progression through the cell cycle are accelerated. We have
previously shown that levels of mRNA encoding Cln3, a G1
cyclin, rapidly increase in response to fresh medium (19). More recently, we have shown that CLN3 transcription is
regulated by carbon source (25) and that regulation of
CLN3 expression plays a role in the regulation of
G1 length in response to nutrient changes (15,
24).
In this work, we show that the level of CLN3 mRNA increases
in parallel with a large-scale increase in total poly(A)+
message in response to glucose. We also show that CLN3 plays a role in the rapid acceleration of growth in response to fresh medium.
We show that ADA2 and ADA3/NGG1 are needed not
only for the rapid increase in CLN3 message but also for the
rapid global transcriptional increase that normally occurs in response
to glucose. ADA2 and ADA3/NGG1 encode
transcriptional adaptor proteins that form large complexes associated
with histone acetyltransferase activity (1, 2, 13, 22, 26,
29). These proteins are believed to play an important role in the
transcriptional regulation of a large number of genes. Surprisingly,
although ADA2 and ADA3/NGG1 were important in the
rapid increase in mRNAs induced by glucose, deletion of ADA2
or ADA3 had relatively little impact on the cellular levels
of these mRNAs over a longer time. This suggests a role for
ADA2 and ADA3/NGG1 in mediating rapid responses.
| |
MATERIALS AND METHODS |
Yeast strains and culture methods.
The S. cerevisiae strains used are listed in Table
1. Deletion of CLN3 in strain
DS10 was done as described elsewhere (5) and confirmed by
Southern and Northern blotting. The ada2 and ada3/ngg1 deletion mutants in the CY232 (21)
background, described in reference 27, were
constructed by using a hisG-URA3 cassette as described
previously (22). The rpd3
strain (DY150) and
the isogenic wild-type strain were provided by David Stillman
(32). Cells were grown in YEPD medium containing 1% yeast
extract, 2% Bacto Peptone, and 2% glucose at 30°C with shaking. The
term "post-log cells" refers to cultures grown for 2 to 3 days in
YEPD to an optical density at 660 nm (OD660) of
approximately 6 to 7.
RNA preparation and blotting.
RNA isolation and blotting
were done as described elsewhere (9). Yeast samples (10 to
15 OD660 U) were collected for RNA preparation, and samples
(15 µg) were run on agarose-formaldehyde gels and transferred to
nylon filters. Blots were probed with a 1-kb EcoRI fragment
of CLN3, a 3-kb HindIII fragment of
BCK2, and a 1-kb BamHI/HindIII
fragment of CDC28 or with a poly(dT) oligomer (15 to 18 nucleotides) end labeled with T4 polynucleotide kinase and
[
-32P]ATP for total poly(A)+ messages. A
0.6-kb SacI fragment was used to probe for U2 RNA as a
loading and transfer control. Uniform loading and transfer of the blots
were confirmed by rRNA staining with ethidium bromide. Blots were
analyzed with a Molecular Dynamics PhosphorImager.
| |
RESULTS |
Role of CLN3 in the yeast response to glucose.
As
cells growing in YEPD pass out of log phase, they enter a slow growth
oxidative phase, in which they tend to accumulate in G1 as
unbudded cells. When these cells are transferred back to fresh medium,
they return to rapid proliferative growth. This is preceded by a rapid
increase in the transcription of CLN3, with a 5- to 10-fold
increase within 5 min (Fig. 1A).
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FIG. 1.
Deletion of CLN3 delays return to
proliferative growth. (A) Cells (TG3) carrying a deletion in
CLN3, along with the isogenic wild-type (WT) strain (DS10)
as a control, were grown for 2 days in YEPD to an OD660 of
approximately 7. Cells were centrifuged and resuspended in fresh YEPD
to an OD660 of 1, and samples were collected for Northern
blotting at the indicated times (minutes) after transfer. In this and
other experiments, we used U2 RNA as a loading and transfer control
because the more commonly used loading standards appear to be induced
when cells are treated with fresh medium. (B) Cells were treated as
described above, and bud counts on triplicate samples were performed at
the indicated times after transfer. At least 300 cells were counted per
time point for each strain. (C) A cyr1 strain (TC41) was
grown for 2 days to post-log phase in YEPD-1 mM cAMP to an
OD660 of 7, transferred into YEP medium lacking both
glucose and cAMP, and incubated overnight. The cells were then
transferred to fresh YEPD without cAMP, and samples were collected at
the indicated times for Northern blotting.
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|
The prominent role that
CLN3 plays in regulating
transcription of Start-specific transcripts (
34,
35)
suggested that the
induction of
CLN3 mRNA might be an
important step in moving out
of G
1 as cells resume rapid
growth. To test this, we measured
the ability of post-log cells
carrying a deletion in
CLN3 to begin
moving through the cell
cycle after transfer to fresh medium (Fig.
1B). Post-log cells were
transferred to fresh YEPD, and bud emergence
was scored at intervals in
triplicate samples to determine how
quickly the cells were able to move
through Start. Compared to
wild-type cells, cells lacking
CLN3 were delayed by one generation,
approximately 90 min,
in returning to proliferative
growth.
The increase in transcript levels in response to glucose is not
restricted to
CLN3 but coincides with an increase in the
level
of a large group of mRNAs that can hybridize with a labeled
poly(dT)
oligomer (Fig.
1A). While we cannot rule out a large-scale
increase
in polyadenylation in this experiment, this change in
poly(A)
+ RNA has been previously shown to correspond to a
change in the
overall rate of mRNA synthesis by RNA polymerase II
(
3). Few
individual bands are observable; however, most of
the hybridization
occurs in the size range between 500 and 4500 nucleotides, clustering
around the 1,000- to 2,000-nucleotide range.
This size range is
consistent with the expected size for most yeast
messages, and
the smeared signal is also consistent with an increase in
the
group of more than 1,000 messages reported to be increased by
glucose (
6). This indicates that
CLN3 is among a
large group
of genes that are induced in response to fresh glucose
medium.
While the increase in
CLN3 transcription in response to
fresh medium coincides with an increase in overall mRNA levels,
CLN3 is not necessary for this increase. Deletion of
CLN3 delayed the
return to proliferative growth, but it did
not prevent the increase
in total mRNA in response to fresh medium
(Fig.
1A). Furthermore,
even though
cln3 cells have a
delay in Start (
4,
23), they
grow at a normal rate after the
initial delay. Both wild-type
cells and cells carrying a deletion in
CLN3 grew in YEPD with
a doubling time of approximately 100 min (not
shown).
Addition of glucose to
S. cerevisiae cells has been shown to
produce a rapid increase in intracellular cyclic AMP (cAMP) levels
(
11), and cAMP levels fall as cells deplete the glucose in
the
medium (
12,
31). To determine whether this increase in
cAMP
is needed for the increase in total mRNA in response to fresh
medium, we used a strain (TC41) carrying a deletion in the gene
encoding adenylate cyclase,
CYR1, in which we can manipulate
cAMP
levels. These
cyr1 cells cannot produce cAMP and
become permanently
arrested in G
1 unless cAMP is added to
the medium. We found that
total mRNA levels responded to glucose in the
complete absence
of cAMP (Fig.
1C). In this experiment, the cells were
grown to
post-log phase in YEPD-1 mM cAMP at an OD
660 of
7. These cells
were largely unbudded (less than 3%). The cells were
then transferred
into YEP medium lacking both glucose and cAMP and
incubated overnight
to ensure that both glucose and cAMP were exhausted
from the medium.
The cells were then transferred into fresh YEPD
without cAMP,
and samples were collected at intervals for Northern
blotting.
Although these cells remained unbudded (less than 3%) in the
absence
of cAMP, they produced an increase in poly(A)
+ RNA
that was similar to that seen in the previous experiment.
Therefore,
the large-scale induction of mRNAs by glucose is cAMP
independent, and
progression through the cell cycle is not necessary
for this response.
We have previously shown that the glucose induction
of
CLN3
is also cAMP independent (
25). Our results are consistent
with the idea that
CLN3 plays an important but not exclusive
role
in moving the cells out of G
1 and through Start as
they resume
proliferative growth in response to fresh medium. Overall,
the
results best fit a model in which fresh glucose medium induces
the
transcription of a large group of genes that are important
in both the
rapid resumption of growth in size and the resumption
of progress
through the cell
cycle.
Deletion of ADA2 or ADA3 inhibits glucose
induction.
The yeast ADA3/NGG1, ADA2, and
GCN5 genes have been implicated in a wide variety of
transcriptional responses (14, 33). The products of these
genes form large complexes that interact with both the general
transcriptional machinery and transactivator proteins. In addition,
these complexes contain histone acetyltransferase activity, which is
thought to play a role in altering chromatin structure at promoters. We
found that deletion of either ADA2 or ADA3/NGG1
strongly inhibited the induction of CLN3 mRNA when fresh
glucose medium was added to post-log cells (Fig.
2A). Deletion of ADA2 or
ADA3/NGG1 also blocked the glucose induction of two other
genes involved in passing Start, CDC28 and BCK2
(8, 10, 28).
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FIG. 2.
Deletion of ADA2 or ADA3/NGG1
inhibits a global transcriptional response to glucose. (A and B)
Post-log wild-type (WT; CY232) and isogenic ada2 and
ada3 mutant cells, as indicated, were transferred to
fresh YEPD at an OD660 of 1, and samples were collected at
the indicated times (minutes) for Northern blotting with probes for
specific messages or with a poly(dT) oligomer for poly(A)+
RNA. Blots A and B are from separate gels using the same RNA source.
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|
A more striking phenotype for the
ada3/ngg1 and
ada2 mutants is shown in Fig.
2B. Deletion of
ADA3/NGG1 also inhibited the
large-scale induction of
transcription produced when glucose was
added to post-log cells. In
wild-type controls, poly(A)
+ RNA increased approximately
fivefold. In contrast, addition of
medium containing fresh glucose to
cells carrying a deletion in
either
ADA2 or
ADA3/NGG1 produced little increase in poly(A)
+
RNA. Thus,
ADA3/NGG1 is required not only for the rapid
glucose
induction of
CLN3 but also for the rapid increase in
transcription
of a large group of
genes.
While the effect
ada2 and
ada3/ngg1 mutants on
the rapid transcriptional response to glucose was quite striking, over
a longer
time course,
CLN3 message and total
poly(A)
+ RNA levels slowly increased toward normal in these
mutants (Fig.
3). When we examined
CLN3 and poly(A)
+ RNA levels in cells growing in
log phase in glucose medium, we
observed little if any difference
between the mutants and wild-type
cells (Fig.
4). This finding indicates that
ADA2 and
ADA3/NGG1 appear to be important in the
kinetics rather than the magnitude
of the transcriptional response to
glucose.
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FIG. 3.
Effect of ADA2 or ADA3/NGG1
deletion transcriptional response to glucose is transitory. Post-log
wild-type (CY232) and isogenic ada2 (A) and
ada3 mutant (B) cells, as indicated, were transferred to
fresh YEPD at an OD660 of 1, and samples were collected at
the indicated times (minutes) for Northern blotting with probes for
specific messages or with a poly(dT) oligomer for poly(A)+
RNA.
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FIG. 4.
ADA2 or ADA3/NGG1 deletions do not
affect CLN3 mRNA or poly(A)+ RNA levels in cells
in log-phase growth. Wild-type (WT; CY232) and isogenic
ada2 and ada3 mutant cells, as indicated,
were grown to mid-log phase in YEPD and collected for Northern blotting
as indicated.
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|
Mutations in RPD3 increase CLN3 mRNA
levels.
The RPD3 gene encodes a protein with histone
deacetylase activity, potentially serving the opposite function of
complexes containing Ada proteins (7, 20, 30). We found that
indeed, deletion of RPD3 produced a very large increase in
CLN3 message levels. In particular, loss of RPD3
prevented the decrease in CLN3 levels normally seen in
post-log cells (Fig. 5). In contrast to
the results with the ADA2 and ADA3/NGG1
mutations, deletion of RPD3 produced little effect on
overall mRNA levels, indicating that RPD3 affects the
transcription of a smaller subset of genes.
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FIG. 5.
Deletion of RPD3 increases CLN3
message levels. (A) Post-log wild-type (DY150) and isogenic
rpd3 (DY1539) cells were transferred to fresh YEPD at an
OD660 of 1, and samples were collected at the indicated
times (minutes) for Northern blotting with a CLN3 probe or
with a poly(dT) oligomer for poly(A)+ RNA. (B) Quantitation
of the CLN3 signal with a Molecular Dynamics PhosphorImager,
normalizing for loading by using the U2 signal. (C) Quantification of
poly(A)+ signal.
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| |
DISCUSSION |
For S. cerevisiae, the presence of a fermentable carbon
source such as glucose in the medium has a profound impact on growth in
mass, cell cycle progression, and gene expression. Very little is known
about the mechanism that produces this response. It is tempting to
speculate about the possible mechanisms that allow such a large group
of genes to be activated by one signal. Glucose produces effects on a
great number of genes with no obvious regulatory features in common.
One possibility for coordinated regulation of these genes would be for
glucose to regulate the activity of the ADA gene products.
This would allow a centrally regulated complex, or set of complexes, to
coordinate the activity of a large group of genes.
The discovery of histone acetyltransferase complexes containing the Ada
proteins has led to models in which these complexes are recruited to
promoter regions in order to alter chromatin structure and increase
transcription. Exactly which genes require these complexes for
activation remains unknown; however, it seems likely that this type of
mechanism is involved in the transcriptional regulation of a wide range
of genes. Our initial results indicate that loss of ADA2 or
ADA3 affects the transcription of enough genes in yeast to
produce a noticeable effect on the total level of poly(A)+
RNA at early time points. Addition of fresh glucose medium to post-log
cells produced a rapid rise in poly(A)+ RNA levels that was
strongly inhibited by loss of either ADA2 or
ADA3. One possible interpretation of these results is that complexes containing Ada proteins are directly involved in the transcription of a substantial fraction of the genes that are upregulated by glucose. Another possibility is that these mutations affect the levels of a key regulator of transcription. In this case,
the effect on induction by glucose would be indirect. Our experiments
do not distinguish between these two models.
While the ADA deletions clearly had an impact on the
transcriptional response to glucose, this effect was only transitory and had all but disappeared by the time that the cells reached log-phase growth. This suggests that an important role for the ADA gene products is one of catalyzing transcriptional
responses that can eventually occur in their absence. Many protein-DNA
interactions occur with very high affinity and consequent slow off
rates. These complexes may be ill suited for rapid changes in response
to regulatory signals. Complexes containing Ada proteins may play an
important role in accelerating this kind of transcriptional response.
Recent work with DNA microarrays has shown that loss of Gcn5, a key
component of the SAGA complex that also contains Ada2 and Ada3,
produces a decrease in the transcription of only about 5% of the genes in S. cerevisiae (17). However, because these
experiments were done with cultures under constant growth conditions,
the microarray results may lead to an underestimate of the importance
of the SAGA complex in transcriptional regulation. It seems possible that while having little effect on the final transcript level, the SAGA
complex may affect the kinetics of transcriptional responses for a much
larger set of genes.
In our hands, the ada2 and ada3 mutants
show a growth lag when inoculated into culture medium, taking
noticeably longer than wild-type cells to enter logarithmic growth.
This may be due to the delay in the transcriptional response to fresh
medium. Other phenotypes such as slow growth, sensitivity to heat, and poor growth on minimal medium (18) may be due to longer-term transcriptional changes produced by the mutations.
The results with the rpd3 mutant indicate that histone
deacetylation plays a major role in decreasing CLN3
transcription, consistent with the previously reported role in
transcriptional repression reported for RPD3. Loss of
RPD3 has been shown to increase overall levels of histone
acetylation, and transcription of CUP1 and PHO5,
suggesting a role in transcriptional repression. However, this simple
model must be qualified by the fact that loss of RPD3 increases telomeric silencing (30). In contrast to the
ADA2 and ADA3 mutations, deletion of
RPD3 had little if any effect on the total
poly(A)+ RNA in the cell, suggesting that Rpd3 regulates a
smaller number of genes than the Ada proteins. This is consistent with
the fact that RPD3 is a member of a family of similar
proteins found in S. cerevisiae. These proteins may regulate
separate subsets of genes.
| |
ACKNOWLEDGMENTS |
We thank Craig Peterson for providing the ADA2 and
ADA3 deletion strains, David Stillman for providing the
RPD3 deletion strain, and Chris Brandl for providing a
NGG1 DNA clone.
This work was supported by Public Health Service grant GM42406 from the
National Institutes of Health.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: School of
Pharmacy, University of Wisconsin, 425 N. Charter St., Madison, WI
53706. Phone: (608) 262-1795. Fax: (608) 262-3397. E-mail:
wheidema{at}facstaff.wisc.edu.
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Journal of Bacteriology, August 1999, p. 4755-4760, Vol. 181, No. 16
0021-9193/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
