[]~EVIEWS
12
13
14
15
16
17
18
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20
2I
22
23
24
25
26
27
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R.D. THOMPSON AND H - H . KIRCtt ARE IN THE MAx-PLANCKINSTITUT F~R Z(,'ICHTUNGSFORSCHUNG, CARL-VON-LINNI~-WEG
10, D-5000 KOLN30, FRG.
T r a n s c r i p t i o n initiation by eukaryotic RNA polymerase II requires many proteins in order to occur in a
specific and regulated fashion. Biochemical studies
have identified numerous factors that are required for
transcription in vitroL These factors can be divided
into different groups. First, the general initiation factors, along with RNA polymerase II, are required at
most or all promoters. Second, many regulatory proteins confer activation or repression of transcription in
a more gene-specific fashion. A third class, called coactivators or adaptors, may mediate interactions between regulatory and general factors 2. Finally, histones
play a role in repression of transcription initiation>5.
Work in yeast, Drosophila, mouse, rat and human systems strongly suggests that transcription initiation is a
highly conserved process throughout eukaryotes.
Genetic studies in the yeast Saccharomyces
cerevisiae have contributed to our understanding of
the complexities of transcription initiation by RNA polymerase II. In many cases, these studies have progressed from the isolation of mutations affecting the
transcription of certain genes to the isolation of extragenic suppressors of the initial mutations. These elaborate genetic analyses have identified genes essential
or important for transcription in vivo. Some of these
genes can be correlated with factors defined by biochemical analyses. However, mutant analysis has also
revealed additional aspects of transcriptional control.
Genetic analyses of three different systems in S.
cerevisiae have converged on factors that are c o m m o n
to all three and have provided insight into an important new facet of transcriptional control. These
systems are: regulation of the H O gene, which is
required for mating type switching; glucose repression
of the SUC2 (invertase) gene; and suppression of
insertion mutations caused by either the transposable
element Ty or a 8 element (a copy of a Ty long
Yeast SNF/SWI
transcriptional activators
and the SPT/SIN
chr0matin connection
FRED WINSTON AND MARIAN CARLSON
Genetic studies of many diversely regulated genes in the
yeast Saccharomyces cerevisiae have identified two
groups of genes with globalfunctions in transcriptio~ The
first group comprises five SNFand SWI genes required for
transcriptional activatiom The other group, containing SPT
and SINgenes, was identified by suppressor analysis and
includes genes that encode histones. Recent evidence
suggests that these SNF/SWIand SPT/SINgenes control
transcription via effects on chromati~ SNF2/SWI2
sequence homologues have been identified in many
organisms, suggesting that the SNF/SWIand SPT/SIN
functions are conserved throughout eukaryotes.
terminal repeat). In each case, the mutant hunts were
intended to identify functions specific for HO, SUC2 or
Ty. Remarkably, these searches yielded overlapping
sets of genes, revealing that HO, SUC2, Ty elements
and many other genes share a set of transcriptional
control functions. Furthermore, suppressor analysis has
suggested that this control is related to chromatin
structure. Brief overviews of the HO, SUC2 and Ty
systems are presented below to introduce the relevant
genes (listed in Table 1) and to outline the genetic
studies that revealed the connections between them.
TIG NOVEMBER1992 VOL. 8 NO. 11
©1992 Elsevier Science Publishers Ltd (UK)
38";
[]~EVIEWS
T a b l e 1.
of ~
activator genes ~
Wt2
SNF5
the ~
7'FT~,
Sick
TYE4
Sick
SNF a n d SWI
and SIN s u p p r e s s o r g e n e s
p~rich:
nuClear~ i z a t i o n
SNp~
Sick
SWI1
SPT4
SPT5
SPI~ ""~
SPTI ~
CRE2
Sick
Acidic
Iq
Metal4~ding m ~
Acidic;
l~lization
Acidic; tiuct~r l ~ t i
H~
Dead
HTAI
, '
SPTt6
S!Nt
HTB~
~
~1
a
]3mad
HealLhy
a
groups based on analysis of interactions with extragenic suppressors 12-14. One group includes
the SNF1 gene, which encodes a
protein kinase. Another group
contains three genes - SNF2, SNF5
and S N F 6 - that affect pleiotropic
phenotypes. Sequence analysis of
SNF2 (Refs 15, 16) revealed that it
is the same gene as SWI2, and
SNF5 is probably the same as
SWIIO (K. Nasmyth, pers. commun.). Selection for suppressors
of snf2 and snf5 yielded mutations in the SSN20 gene, which
also suppress snf6 (Refs 13, 14).
SSN20 is the same as SPT6, a gene
described below that affects Tyand 8-mediated gene expression.
. . . . . . Histone H2B
Acidic
HMGl-likei
Historm H
lo¢.aUzation
Suppressors of Ty and 8 insertion
mutations
Insertion mutations in the 5'
regions of genes, caused by Ty elements or 8 sequences, often
abolish or otherwise alter transcription of the adjacent gene.
These effects are believed to be
due to interference or competition by transcription
signals in the Ty or 8 sequence with those of the adjacent gene. For example, for a 8 insertion mutation at
the HIS4 gene, transcription initiates in the upstream
8 sequence, rather than at the normal HIS4 initiation
site; this change results in a nonfunctional HIS4 mRNA
and a His- phenotype. Selections for extragenic suppressors of Ty and ~5 insertion mutations have identified a large number of genes (SPT, for suppressor of
Ty) 17,1s. In all spt mutants examined, transcription initiating in Ty elements or solo 8 sequences is reduced,
and normal transcription of the adjacent gene is restored. Therefore, SPT functions somehow affect the
competition between transcription signals in the Ty
and 8 elements, and those of the adjacent gene.
Many of the SPT genes have been identified in
other genetic and biochemical studies, suggesting roles
in transcription of many genes. Two of the SPTgenes,
SPT11/HTA1 and SPT12/I-ITB1, encode histones H2A
and H2B, indicating that chromatin structure plays a
role in transcription initiation 19. Analysis of spt mutant
phenotypes indicated that at least four other SPTgenes
of unknown function, including SPT6/SSN20, are functionally related to SPT11 and SPT12; these genes will be
called the 'histone group' of SPTgenes and will be discussed in this review. Other SPTgenes include SPT15,
which encodes the general transcription factor TFIID;
studies of different TFIID mutants have suggested that
they cause alterations in transcription either by altered
binding to DNA or by an impaired interaction with at
least one other transcription factor.
I null mutation in
mutations ~
Regulation
of riO
transcription
The HO gene encodes an endonuclease that is
required for mating type switching. This gene is subject to many types of transcriptional regulation. The
regulation can explain most of the observed patterns
of mating type switching with respect to cell cycle
control, mating type control, and the ability of mother
cells, but not daughter cells, to switch 6.
Early studies identified ten genes (SW/, for switch)
that are important for HO transcription 7,8. The swi mutations are pleiotropic, suggesting that they also affect
transcription of other genes. The isolation of suppressors of swi mutations identified other genes, designated SIN or SDI (hereafter referred to as SIN, for switch
independent)9,10. The analysis of sin mutant phenotypes and the interactions of different sin and swi mutations led to models for each aspect of the control of
HO transcription. In these models, SWI proteins are
positive activators of HO transcription and SIN proteins
are repressors (for a review, see Ref. 11). This genetic
analysis divided the SW/genes into different functional
groups that have been extensively studiedg. The group
comprising three of these SW/genes - SWI1, SWI2 and
SWI3 - will be discussed here.
Control o f s u e 2 transcription
The SUC2 gene encodes invertase, the enzyme required by S. cerevisiae to catabolize sucrose or raffmose.
SUC2 is regulated at the transcriptional level by glucose
repression: SUC2 transcription is repressed in growth
media containing high glucose and is derepressed in
media with limiting glucose. Mutations that reduce or
abolish transcription of SUC2 under derepressing conditions have been isolated, thereby identifying genes
(SNF, for sucrose nonfermenting) that are required for
SUC2 transcription 12. The SNF genes were divided into
Common factors with multiple aliases controlHO,
and Ty transcription
SUC2
An important breakthrough in understanding the
relationship between SUC2 and Ty transcription came
TIG NOVEMBER1992 VOL. 8 NO. 11
~88
~EVIEWS
from the genetic mapping and molecular analysis that
demonstrated that SPT6 and SSN20 are the same
gene 2°,21. This result led to the finding that SNF2, SNF5
and SNF6 are required for Ty transcription 22,23. Since
SPT6 was a member of the 'histone group' of SPT
genes, the identity of SPT6 and SSN20 suggested that
mutations in other members of this SPT group also
might suppress snf2/swi2, snf5 and snf6 mutations. This
hypothesis proved correct: mutations in SPT4, SPT5,
SPT6, SPT11/HTA1, SPT12/HTB1 and SPT16/CDC68 all
suppress the defects in Ty and SUC2 transcription
caused by snf2 and, in most cases that have been
tested, they also suppress snf5 and snf6 (Refs 24, 25).
A second important connection was the discovery,
from DNA sequence analysis, that SNF2 and SWI2 are
the same gene. This result linked HO with SUC2 and
Ty, suggesting that all are controlled by common
factors.
SNF and SWI genes encode transcriptional activators
Evidence from several labs indicates that
SNF2/SWI2, SNF5, SNF6, SWI1 and SWI3 are required
for transcription of many diversely regulated genes.
Independent studies of the SNF and SW/genes had
identified large sets of genes subject to their control.
The discovery that SNF2 and SWI2 are the same gene
appears to merge these sets. SNF2/SWI2, SNF5 and
SNF6 were shown to be required not only for SUC2
and Ty expression, but also for normal expression of
acid phosphatase, growth on nonfermentable carbon
sources, sporulation, and some cell-type specific functions 15,26. In addition, SNF2/SWI2 and SNF5 affect protease B expression 27. SWI1, SNF2/SWI2 and SWI3 were
shown to affect HO and IN01 (inositol-l-phosphate
synthase) transcription, growth on limiting leucine,
and sporulation 7,28. Recent evidence confirms that all
five SNF/SWI genes are required for normal transcription of ADH2 (alcohol dehydrogenase), GALl (galactokinase), SUC2, IN01 and HO (Ref. 29).
Studies of SNF2/SWI2, SNF5 and SNF6 have
directly implicated these proteins in transcriptional
activation. The SNF2/SWI2 and SNF5 proteins were
fused to the DNA-binding domain of the E. coil LexA
protein, yielding bifunctional LexA-SNF hybrids. These
hybrid proteins activated transcription of a target promoter in vivo when bound to a lexA operator15, 26.
Importantly, activation by LexA-SNF2/SWI2 requires
SNF5, SNF6 and SWI1, and activation by LexA-SNF5
requires SNF2/SWI2, SNF6 and SWI1 (Refs 15, 30).
These results strongly argue for a functional interdependence among these SNF and SWI proteins. In
contrast, a LexA-SNF6 fusion protein activates transcription independently of SNF2/SWI2, SNF5 and SWI1
(Ref. 30). Thus, SNF6 may play a more direct role in
stimulating the transcriptional apparatus.
The predicted SNF/SWI protein sequences contain
no motifs strongly indicative of DNA binding (Table 1),
and no experimental evidence has been obtained for
DNA binding by these proteins 15,26,29. Therefore, the
native SNF/SWI proteins may be directed to particular
promoters via interactions with other proteins that
bind to DNA.
The effects of SNF and SWI proteins on expression
of diversely regulated genes suggested that these
proteins may act coordinately with various gene-specific
regulators that have DNA-binding activity. Indeed, recent studies of gene-specific activators in snf and swi
mutants support this idea. First, the ability of GAL4 to
activate via a minimal UASGAL (upstream activation sequence) is reduced in a swil mutant; control experiments suggest that this effect does not result from a
defect in expression of GAL4 (Ref. 29). Also, the ability
of the Drosophila fushi tarazu (ftz) protein, when expressed in yeast, to activate a target gene with ftzbinding sites is reduced in a swil mutant 29. In a separate study, GAL4 and the Drosophila bicoid protein
(which activates in yeast) were tested for dependence
on SNF2/SWI2, SNF5 and SNF6. Transcriptional activation by LexA-GAL4 and LexA-bicoid depends on
SNF2/SWI2, SNF5 and SNF6; however, the degree of
dependence varies with the two activators, the number
of LexA-binding sites available for the activator and
the target promoter 30. Finally, transcriptional activation
in yeast by glucocorticoid receptor requires SNF/SWI
proteins (S. Yoshinaga, C. Peterson, I. Herskowitz
and K. Yamamoto; cited in Ref. 29). Thus, the SNF and
SWI proteins may represent a class of intermediary
proteins that help gene-specific regulators to activate
at certain promoters.
The similar phenotypes of snf/swi single and triple
mutants 29 and their functional interdependence in the
LexA assay system 15 suggest that all five genes interact
in some way to affect transcription. Certain models,
such as transcriptional cascades involving different
SNF/SWI genes, have been ruled out. Some evidence
points towards the existence of a SNF/SWI heteromeric
complex: the activation properties of the LexA-SNF
proteins 153°, and the decreased stability of the SWI3
protein in a swil snf2/swi2 double mutant 29. Definitive
evidence that some or all of these proteins physically
interact will require biochemical studies.
Suppressors ofsnf/swi mutations: a chromatin
connection
Mutations in several genes have been identified that
can suppress snf and swi mutations and restore gene
expression. These suppressors appear to inactivate
functions that repress transcription, thereby alleviating
the requirement for SNF/SWI proteins. Analysis of these
suppressors suggests that activation of transcription by
SNF2/SWI2, SNF5, SNF6, SWI1 and SWI3 involves
changes in chromatin from an inactive to an active state.
This model was initially based on the discovery that
mutations in SPTI1/HTA1 and SPT12/HTB1, one of the
two gene pairs encoding histones H2A and H2B, suppress mutations in snf2/swi2, snf5 and snf6 (Ref. 25).
Recent evidence has demonstrated that the chromatin
structure of the SUC2 promoter differs in SNF + and sn/
strains when they are grown under conditions normally
derepressing for SUC2 transcription2531 and has strongly
suggested that this change in chromatin structure causes
a change in the level of SUC2 transcription 25.
Analysis of the sinl and sin2 suppressors of swil,
snf2/swi2 and swi3 mutations has also implicated chromatin structure as a target of SWI1, SNF2/SWI2 and
SWI3 functions. Recently, it has been shown that SIN2
is the same as HHT1, one of two genes of S. cerevisiae
that encodes histone H3 (W. Kruger, C. Peterson, A. Sil
TIG NOVEMBER1992 VOL.8 NO. 11
[]~EVIEWS
and I. Herskowitz, unpublished). SIN1, the same gene
as SPT2, encodes a protein that is similar to HMG1
proteins and binds to DNA in a nonspecific fashion32.
sinl/spt2 mutations suppress defects caused by the
deletion of part of the carboxy-terminal domain (CTD)
of the largest subunit of RNA polymerase II, suggesting
a possible link between the CTD and overcoming
repression by chromatin 28.
The common phenotypes caused by mutations in
the 'histone group' of SPT genes strongly suggest that
the members of this group that do not encode histones
are also involved in controlling transcription via
changes in chromatin structure. Although their functions are not known, several lines of evidence suggest
that the SPT4, SPT5 and SPT6 proteins form a complex: double mutant combinations are generally lethal;
recessive mutations in these genes fail to complement;
altered SPT5 or SPT6 gene dosage causes an
Spt- phenotype; and SPT5 and SPT6 coimmunoprecipitate33. Such a complex might have roles in
assembly of histones into nucleosomes, similar to the
CAF-1 function found in HeLa cells34, or in maintaining
chromatin in an inactive state, as proposed for the
Polycomb group of genes of Drosophila35 (see below).
SNF2/SWI2 is widely conserved in eukaryotes
Genes that encode proteins strikingly similar to
SNF2/SWI2 have recently been identified in S. cerevisiae, Drosophila, the silk moth Bombyx mori, mouse
and human3~,-39. Some of these sequence homologues
may prove to be functional homologues. One of
the Drosophila SNF2/SWI2 homologues, brahma (brm),
is required for activation of many genes, including
several homeotic genes of the Antennapedia complex and the Bithorax complex37, brm was initially
identified as one of many extragenic suppressors of
mutations in Polycomb (Pc) 40. Pc, along with other
genes that have mutant alleles conferring similar
phenotypes (the Pc"group genes), is believed to be required to maintain a spatial restriction of gene expression via an effect on chromatin35. An analogy can
be made, then, between the brm and SNF/SWI proteins as activators and between the Pc group and
SPT/SIN proteins as functions that may repress via
chromatin. Interestingly, the suppression relationships
in the two systems are reversed: brm mutations suppress Pc" mutations, while spt/sin mutations suppress
snf/swi mutations. This difference probably reflects different regulation of the genes whose expression was
studied: in Drosophila, genes that are normally repressed; in yeast, genes that are expressed under
many conditions.
The other S. cerevisiae genes with sequence similarity to SNF2/SWI2 include MOT1, STH1, RAD16 and
RAD54, some of which appear to function in transcription. MOT1 is an essential gene identified by a mutation, mot1-1, that allowed transcription from a promoter in the absence of a required activator38. STH1
was cloned by homology to SNF2/SWI2 and is
essential for growth; however, STH1 is functionally
distinct from SNF2/SWI2 (Ref. 36). RAD16 and RAD54
are involved in DNA repair; whether they function
directly in repair or regulate transcription of other
genes required for repair is not known 39.
SNF2/SWI2 defines a family of structurally related
proteins that have sequence similarity to helicases
An important recent finding is that the SNF2/SWI2
homologues contain sequences resembling the consensus motifs found in helicases 363~. The conserved sequences appear to define a new family of helicaserelated proteins. The possibility that these proteins
have helicase activity can be tested and it raises the exciting prospect of having a biochemical handle on the
functions of the SNF/SWI proteins. Possible roles for
such a helicase activity have been proposed 41. Many
questions need to be addressed: What is the specificity
for nucleic acid? What is the site of action and how is
it specified? Does SNF2/SWI2 helicase activity require
other SNF/SWI proteins? An appealing model is that
the predicted helicase activity of SNF2/SWI2 is required for changing the conformation or position of
nucleosomes or other DNA-binding proteins to provide access for either activators or general transcription
factors. However, it is by no means clear that all members of this family of presumed helicases will be involved in the same aspects of gene expression.
Conclusions and perspective
The studies reviewed here provide insight into the
functions of SNF/SWI and SPT/SIN proteins in transcriptional control. The SNF2/SWI2, SNF5, SNF6, SWI1 and
SWI3 proteins are required for transcriptional activation
of a large set of diversely regulated genes. Some or
all of the five SNF/SWI proteins may function in a heteromeric complex. The requirement for the SNF/SWI
activators is suppressed by mutations in SPT/SIN genes
that encode histones or that are implicated in affecting
chromatin structure. Therefore, SNF/SWI proteins may
function by overcoming an inactive or repressed
chromatin state that is caused by the SPT/SIN proteins
(Fig. 1). In this model, the SNF2/SWI2 helicase activity
plays a central role in chromatin remodeling.
The SNF/SWI proteins may also play another, more
direct role in transcriptional activation, as LexA-SNF
proteins are capable of activating transcription. Since
SNF/SWI proteins are also required for activation
by gene-specific activators such as GAL4, the native
SNF/SWI proteins may work together with genespecific activators to achieve maximal levels of transcription. Evidence for a dual role for transcriptional
activators, both in direct activation and in overcoming
repression by histones, has recently come from
biochemical studies 42,43. We propose that the SNF/SWI
proteins may function in conjunction with genespecific activators in both roles. The relationship of
SNF/SWI proteins to a class of intermediary transcription factors that have been defined biochemically coactivators or adaptors 2 - remains to be clarified.
In summary, the SNF/SWI and SPT/SIN proteins,
identified by genetic approaches, play an important role
in transcriptional control. Biochemical studies are now
needed to elucidate important aspects of their functions,
including their sites of action, interactions with other
proteins in transcription initiation, and effects on
chromatin. In addition, possible roles in establishment
or maintenance of an altered chromatin state need
to be distinguished. Preliminary indications are that
the SNF/SWI and SPT/SIN functions may be highly
TIG NOVEMBER 1 9 9 2 VOL. 8 NO. 11
$90
[]~EVIEWS
conserved
throughout
the
eukaryotic world. Thus, these
genetic studies in yeast should
provide a basis for understanding important features of transcription in other eukaryotes.
F and SWI protein~
overcoming inactive chromatin
Acknowledgements
We thank Joel Hirschhorn,
Brehon Laurent and Lena Wu for
helpful comments on this manuscript. We apologize to those
whose work was not cited due to
space restrictions. Work from our
labs was supported by grants from
the NIH and the American Cancer
Society.
direct
activation
J repressionvia inactivechromatin
i J HO, SUC2,Ty,
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SCHOOL,25 SHA~CK STREET,BOSTON,MA 02115,
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USA; M. CARLSON I$ IN THE DEPARTMENTS OF GENETICS AND
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DEVELOPMENT AND MICROBIOLOGY~ AND THE INSTITUTE OF
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CANCER RESEARCH~ COLUMBIA UNIVERSITY COLLEGE OF
(1991)/14ol. CellBiol. 11, 5710-5717
PnYSlaANS
AND SURGEONS, NEw YORK, NY 10032, USA.
25 Hirschhorn, J.N., Brown, S.A., Clark, C.D. and Winston, F.
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