Adolf-Butenandt-Institut, Schillerstraße 44,
München 80336, Germany
*
Author for correspondence (e-mail:
Peter.Becker{at}mol-bio.med.uni-muenchen.de
)
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SUMMARY |
---|
Key words: ISWI, Chromatin remodeling, Nucleosome assembly
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Introduction |
---|
|
The first hint of a role for nucleosome-remodeling during gene activation
came from genetic analyses in yeast. Different screens had identified the
SWI/SNF proteins as global regulators of transcription and these were later
shown to reside in one large, 2 MDa complex (Peterson,
2000; Vignali et al.,
2000
). The function of this
complex was linked to chromatin when histones and other chromatin components
were identified as suppressors of the swi/snf phenotype (Winston and Carlson,
1992
). Further analyses showed
that the SWI/SNF complex is necessary to relieve chromatin-mediated repression
of a set of inducible genes and is particularly important for those genes that
are transcribed in late anaphase, when the mitotic condensation of chromatin
is still not fully reversed (Krebs et al.,
2000
). Biochemical analyses of
purified yeast SWI/SNF complex and its human counterpart demonstrated that the
machinery can modulate histone-DNA interactions such that the accessibility of
nucleosomal DNA is much enhanced, facilitating the interaction of proteins
with their binding sites on DNA. The SWI2/SNF2 subunit of the SWI/SNF complex,
a protein that has similarity to DNA helicases, proved to be responsible for
the ATP-dependent nucleosome disruption. Structural and functional homologs of
this ATPase reside in related remodeling machineries in all higher eukaryotes
(reviewed by Muchardt and Yaniv,
1999
). The SWI/SNF complex and
the related human BRM and BRG1 complexes have since been shown to be involved
in many important processes involving chromatin substrates, such as
transcription that leads to cell cycle progression (Muchardt et al.,
1998
), cellular
differentiation (de La Serna et al.,
2001
), replication (Flanagan
and Peterson, 1999
),
recombination (Kwon et al.,
2000
) and repair (Ura et al.,
2001
).
ATP-dependent nucleosome-remodeling was also discovered by an entirely
independent and purely biochemical approach. Wu, Becker and colleagues
screened crude (and enzymatically rich) Drosophila embryo extracts
for activities that allow transcription factors to access nucleosomal binding
sites in vitro (Tsukiyama et al.,
1995; Varga-Weisz et al.,
1997
). Whereas the wrapping of
DNA around the histone octamer frequently prevents the interaction of proteins
with recognition sequences, access of a variety of proteins was virtually
unhindered in the presence of embryo extract. When the transcription factors
gained access to DNA, the nucleosome that had occupied the site before could
no longer be detected by footprinting assays. The realization that this
mysterious `nucleosome remodeling' required ATP hydrolysis triggered a hunt
for energy-dependent nucleosome-remodeling enzymes in the extract, which led
to the identification of two novel complexes (Tsukiyama and Wu,
1995
; Varga-Weisz et al.,
1997
). In a parallel effort,
Kadonaga et al. fractionated the embryo extracts into components required for
the assembly of regularly spaced nucleosomal arrays. The ATP-consuming
`spacing factor' (see below) was also able to facilitate the interaction of
DNA-binding proteins with nucleosomal DNA (Ito et al.,
1997
). Remarkably, all three
factors isolated contained ISWI, an ATPase that had been identified earlier on
the basis of sequence similarity to the SWI2/SNF2 homolog in
Drosophila, Brahma (BRM) and was therefore called
Imitation SWItch (Elfring et al.,
1994
).
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SWI2/SNF2 belongs to the DEAD/H superfamily of nucleic-acid-stimulated ATPases |
---|
|
Since SWI/SNF-type remodeling machines were the first to be identified, a wealth of biochemical and functional data has accumulated. Less is known about ISWI-containing remodeling factors. However, during the past three years a considerable body of data has accumulated, demonstrating that the two types of remodeling machines are functionally distinct. Here we summarize recent data on the ISWI group of remodelers and their function in chromatin dynamics and organization.
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ISWI powers several nucleosome-remodeling machines |
---|
|
ACF was discovered in the Kadonaga laboratory during a systematic
fractionation of the embryo extracts for components required for the assembly
of nucleosomal arrays that have a regular spacing. However, not only can ACF
catalyze the establishment of regularity within an unordered succession of
nucleosomes, but it can also mobilize nucleosomes to facilitate the
interaction of DNA-binding proteins (Ito et al.,
1997). In ACF, ISWI associates
with Acf1, a 170 kDa factor featuring a bromodomain and PHD fingers (Ito et
al., 1999
).
Our group purified dCHRAC from an activity that promoted a global,
energy-dependent increase in accessibility of chromatin (Varga-Weisz et al.,
1997). The earlier hypothesis
(reflected in the name) that such an activity should somehow `crack chromatin
open' was challenged by the observation that CHRAC can also function as a
nucleosome-spacing factor and hence play a role during chromatin assembly.
CHRAC is related to ACF, since it also contains Acf1 (Eberharter et al.,
2001
). In addition, however,
CHRAC also contains the novel histone-fold proteins CHRAC-14 and CHRAC-16
(Corona et al., 2000
; see
Fig. 3). Because of its
extensive copurification and co-immunoprecipitation we originally suggested
that topoisomerase II (Topo II) is a subunit of dCHRAC (Varga-Weisz et al.,
1997
); however, TopoII can be
separated from CHRAC without affecting CHRAC function or integrity (Eberharter
et al., 2001
).
Homology searches led to the identification of two ISWI homologs in yeast
(yISW1 and yISW2) and mammals (SNF2h and SNF2L), as well as a Xenopus
ISWI homolog. The yeast enzymes form two distinct complexes (Tsukiyama et al.,
1999; see
Fig. 3). In frogs, at least
four different complexes exist, the simplest one being of the ACF type
(Guschin et al., 2000a
).
Besides hCHRAC (Poot et al.,
2000
), several ACF-like
complexes have been identified in human cells (Bochar et al.,
2000
; LeRoy et al.,
2000
). Acf1 is a member of a
growing family of proteins that have similar domain architectures (Bochar et
al., 2000
; Jones et al.,
2000
; Poot et al.,
2000
), including WSTF, whose
gene is invariantly deleted (among others) in the genome of William-Beuren
syndrome patients (Peoples et al.,
1998
). Association of ISWI
with a novel, 300 kDa protein produces the remodeling and
spacing factor (hRSF; LeRoy et al.,
2000
).
The analysis of the activity of recombinant Drosophila ISWI
expressed in bacteria and therefore removed from the context of other subunits
demonstrated that the enzyme, in principle, can trigger a
nucleosome-remodeling reaction. Its ATPase activity is stimulated maximally by
the presence of nucleosomes and it is able to catalyze basic
nucleosome-remodeling and -spacing reactions (see below; Clapier et al.,
2001; Corona et al.,
1999
;
Längst et al.,
1999
). However, the activity
of ISWI is stimulated substantially (Ito et al.,
1999
; Hamiche et al.,
1999
;
Längst et al.,
1999
; Eberharter et al.,
2001
) and modulated
qualitatively (Eberharter et al.,
2001
) by other subunits within
the remodeling complexes. ISWI has never been isolated on its own from a
physiologically relevant source following a functional assay. Most, if not
all, ISWI is therefore probably associated with other proteins in the
cell.
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Genetic analyses suggest complex functions for ISWI |
---|
Drosophila lacking ISWI die in the late larval or early pupal
stage, presumably because maternal RNA and protein still supports development
until then. This allows visualization of the polytene chromosomes of dying
larvae. Remarkably, the X chromosome appears severely distorted in male mutant
cells, whereas normal X chromosome morphology is observed in female cells. In
flies the male X chromosome is targeted by the dosage-compensation machinery,
which leads to hypertranscription of many X-linked genes throughout the
chromosome. This involves the loosening of chromosome structure by
site-specific histone acetylation. In the absence of ISWI, the structure of
this `sensitized' chromosome is no longer maintained, which points to a
requirement for ISWI for organization of higher-order chromatin folding
(Deuring et al., 2000).
In contrast to the lethal phenotype in flies, no significant phenotype is
evident in yeast lacking either ISW1 and ISW2 under normal
growth conditions, although transcription of a number of genes is altered
(Hughes et al., 2000).
ISW1 and ISW2 homozygous mutants exhibit defective early
stages of sporulation (Trachtulcova et al.,
2000
). Tsukiyama and
colleagues noted that in an ISW2 mutant several meiosis-specific
genes are derepressed under normal growth conditions (Goldmark et al.,
2000
). They found that
repression of the meiotic REC104 promoter involves the targeting of
the ISW2 complex to the promoter through direct interaction with the
sequence-specific Ume6p repressor. Ume6p requires the ISW2 complex to
establish a repressive chromatin structure, which is further stabilized by
deacetylation by the RPD3-SIN3 deacetylase complex. Targeting of the
nucleosome remodeler correlates with altered nucleosomal positions. Kent et al
recently showed that specific nucleosome positioning at several promoters
depends on ISW1, ISW2 or both ATPases (Kent et al,
2001
). The concept that
emerges from these analyses of physiological chromatin structure is that
ISWI-containing nucleosome-remodeling factors are involved in the
(re)positioning of short arrays of nucleosomes at regulatory sites and is
consistent with their biochemical identification as nucleosome mobilizers.
![]() |
Chromatin remodeling increases factor access and repositions nucleosomes |
---|
As DNA-binding proteins gain access to their binding sites, the nucleosomes
that previously occupied the position are remodeled such that they can no
longer be detected. However, neighboring nucleosomes are also affected:
frequently, randomly positioned nucleosomes acquire an optimal distance from a
DNA-bound protein (Längst et al.,
1998;
Längst et al.,
1999
; Pazin et al.,
1997
; Tsukiyama and Wu.,
1995
; Varga-Weisz et al.,
1995
; Wall et al.,
1995
). This phenomenon shows
that nucleosomes that have been a substrate for ATP-dependent remodeling are
not irreversibly disassembled, but instead repositioned.
![]() |
Some ISWI remodelers can improve the regularity of nucleosomal arrays |
---|
The question of what `spacing' of nucleosomes means in mechanistic terms
still has not been conclusively answered (Varga-Weisz and Becker,
1998). Regularity might be
established simply through relocation of nucleosomes to facilitate their
setting in a regular array of presumed low energy. However, `spacing factors'
might have an additional positive role in the assembly of nucleosomes (Ito et
al., 1999
; see
Fig. 4). The observation that
the higher-order folding of the acetylated male X chromosome in
Drosophila is disrupted in the absence of ISWI (Deuring et al.,
2000
) lends further support to
the Janus nature of ISWI remodelers: they may be involved in the assembly of
folded chromatin but at the same time assure that the resulting structure
remains flexible rather than static.
|
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ISWI complexes facilitate the sliding of histone octamers |
---|
Other remodeling ATPases, such as the CHD-type ATPase Mi-2 and the SWI/SNF
complex, also facilitate nucleosome sliding on linear DNA (Brehm et al.,
2000; Guschin et al.,
2000b
; Whitehouse et al.,
1999
). Recombinant ISWI is
also able to mobilize nucleosomes, but interestingly the outcome of such
mobilization differs when ISWI and CHRAC are compared. Whereas CHRAC is able
to move a nucleosome from one end to a more central position of a DNA fragment
(but not back), ISWI triggers the converse reaction, the sliding of a
nucleosome from the middle of a fragment to its end
(Längst et al.,
1999
). Clearly, at least one
other subunit modulates the outcome of ISWI-induced nucleosome remodeling.
This factor has recently been identified as Acf-1, the largest subunit of
CHRAC and ACF. Association of Acf-1 with ISWI not only stimulates the activity
of ISWI by an order of magnitude but also reverses the directionality of
nucleosome sliding to resemble the CHRAC-type mobility (Eberharter et al.,
2001
). Acf-1 therefore
provides an example of regulation of a core remodeling machinery by
protein-protein association.
![]() |
Mechanistic considerations |
---|
How, then, could nucleosome mobility be facilitated? And why does
mobilization lead to directional nucleosome movements? The observed
stabilization of the histone octamer by ISWI and CHRAC (Varga-Weisz et al.,
1997;
Längst et al.,
1999
) and the fact that no
histone transfer is detected argues against a disassembly model that invokes
complete or partial disassembly of the histone octamer. The situation may be
different for SWI/SNF-induced nucleosome remodeling, in which, particularly at
high enzyme concentrations, transfer of histones to competitor DNA can be
observed (Lorch et al., 1999
;
Phelan et al., 2000
).
SWI/SNF-type remodeling leads to prominent perturbation of histone-DNA
interactions, as determined by DNaseI footprinting and an obvious reduction of
constrained superhelicity - phenomena that so far have not been documented for
ISWI-type remodelers.
Three model scenarios for nucleosome repositioning can be envisaged:
spooling, twisting and bulging (Fig.
5). The `spooling model' (Pazin and Kadonaga,
1997) was inspired by
experiments that monitored the transcription of RNA polymerases through
nucleosomes (Bednar et al.,
1999
; and references therein).
In this scenario the movement of the enzyme on DNA leads to the peeling off
the histone octamer surface of larger DNA segments. The patch of free histone
is then available to capture a different DNA segment (see
Fig. 5). The `twisting model'
argues that ISWI alters the topology of DNA and thereby changes histone-DNA
interactions (Havas et al.,
2000
; Varga-Weisz and Becker,
1998
). As discussed by van
Holde and Yager, thermal energy could alter the twist of DNA (van Holde and
Yager, 1985
), effectively
disrupting a set of DNA-histone interactions at the site of entry into the
nucleosome and replacing them by analogous interactions involving the
neighboring base-pair. Since small distortions of the helix geometry can be
accommodated in the nucleosome (Luger and Richmond,
1998
), it is possible that the
locally altered twist is propagated over the surface of the nucleosome (twist
diffusion). Once the helix distortion emerges on the other side of the
nucleosome, the DNA will have been displaced by one base pair relative to the
octamer surface (see Fig. 5).
The `bulging model' combines aspects from both spooling and twisting models.
In analogy to the spooling model ISWI would disrupt histone-DNA interactions,
but, as in the twisting model, only the first contact of the DNA helix at the
edge of the nucleosome would be affected. The free histone valency would then
interact with DNA one helical turn `outside' of the nucleosomal realm,
effectively bulging out a short DNA segment on the surface of the histone
octamer. Propagation of this `bulge' over the nucleosome surface would lead to
displacement of the DNA relative to the histones. Whereas the twisting model
predicts that the `unit length' of nucleosome mobility would be a single base
pair as the DNA is screwed over the histone surface, a bulging model would be
more consistent with a unit length of mobility of a DNA helix turn (
10.5
base-pairs), and the mobility could be broken down to steps of translational
rather than rotational translocation of the DNA relative to the histone
octamer.
|
Recently, Owen-Hughes and colleagues have shown that a variety of
remodeling machines, including recombinant ISWI, are able introduce negative
superhelicity into linear DNA fragments (Havas et al.,
2000), suggesting that these
machines alter the twist of DNA and at the same time constrain the resulting
superhelical stress within a topological domain. Remarkably, recombinant ISWI
was able to induce local DNA supercoils only in the presence of nucleosomes,
which is consistent with the fact that its ATPase activity is largely
stimulated by nucleosomes. This result could indicate that ISWI needs direct
histone contact in order to twist DNA. Alternatively, the nucleosome could
itself participate in the formation of a topological domain that allows the
accumulation of superhelical stress. By contrast, the SWI/SNF complex is able
to generate superhelicity even in the absence of nucleosomes, possibly through
its ability to bind two DNA segments and constrain the intervening DNA into a
tight loop (Bazett-Jones et al.,
1999
).
Enzyme-substrate interactions
Intuitively one might assume that an enzyme that alters the position of DNA
relative to a histone octamer might have to contact both components and move
them relative to each other. There is indeed evidence for both types of
interaction. ISWI binds only poorly to nucleosomal cores but interacts well
with particles that contain additional linker DNA (Brehm et al.,
2000). A domain that might
mediate DNA binding is its SANT domain, which resembles the DNA-binding
domains of some transcription factors (Aasland et al.,
1996
). An interaction with
histone can be inferred from the recent observation that deletion of the H4
N-terminal tail from nucleosomes prevents ISWI from recognizing the substrate
(Clapier et al., 2001
).
The role of ATP hydrolysis
How might ATP hydrolysis drive nucleosome mobility? Several scenarios can
be envisioned. ISWI might hydrolyze ATP to power a molecular motor that
promotes its translocation on DNA - by analogy with helicases and polymerases.
If ISWI is immobile, as footprinting experiments using nucleosomal substrates
suggest (G.L. and P.B.B., unpublished), it might hydrolyze ATP to twist DNA,
thereby converting the chemical energy of ATP into superhelical stress, which
could lead to dissociation of a segment of DNA from the histone surface.
Theoretically, however, ISWI does not need to manipulate the nucleosome in any
active manner. Since thermal energy suffices to untwist the loosely attached
DNA at the point of entry into the nucleosome, ISWI might simply endow the
natural `twist diffusion' with directionality. In any case, the binding of ATP
is likely to influence the way that ISWI interacts with the nucleosomal
substrate. Nucleotide binding, subsequent hydrolysis and nucleotide exchange
might constitute a cycle of enzyme conformations that in turn determine
distinct interactions with the nucleosome.
Directionality
The observation that Acf-1 is able to improve the efficiency and alter the
directionality of ISWI-induced nucleosome sliding in vitro is intriguing
(Eberharter et al., 2001).
Despite the non-physiological nature of short chromatin fragments, the results
still indicate profoundly different interaction of the remodeling factor with
the nucleosome. Since bromodomains exhibit a preference for binding to an
acetylated isoform of the H4 N-terminus (Owen et al.,
2000
), Acf-1 activity might be
modulated by stable modification of the H4 N-terminus. Whether the PHD fingers
and the WAC domain of Acf-1 contribute to the remodeling mechanism, or
function in complex assembly and/or targeting of the enzyme to specific
nuclear compartments, remains to be determined. It is already becoming clear
that the result of nucleosome mobilization is a function of histone-DNA
interactions (which are in turn determined by DNA sequence and curvature) and
enzyme-DNA interactions.
Not all remodeling enzymes are equal
Although ATPases of the ISWI, CHD and SWI/SNF classes can all catalyze
nucleosome sliding, the substrate requirements differ for each enzyme. The
ATPase of the SWI/SNF complex is already maximally stimulated by free DNA
(Boyer et al., 2000) and can
induce superhelicity into DNA in the absence of histones (Havas et al.,
2000
). Nucleosome remodeling
by SWI/SNF does not require histone N-termini (Boyer et al.,
2000
). Mi-2 represents a
different case: its ATPase is stimulated by nucleosomal DNA but not at all by
free DNA and yet histone N-termini are dispensable for remodeling (Brehm et
al., 2000
). The ATPase of ISWI
is partially activated by DNA and further stimulated by nucleosomes. However,
deletion of the H4 tail abolishes the recognition of the nucleosome substrate
(Clapier et al., 2001
; see
Fig. 6). There are other
indications that nucleosome remodeling by ISWI differs fundamentally from
SWI/SNF-type remodeling. High concentrations of the latter type of factor
eventually lead to eviction of nucleosomes from the DNA fragment and to the
accumulation of nucleosomes that have stable structural changes and resemble
`dinucleosome particles' in many respects (Lorch et al.,
1998
; Lorch et al.,
1999
; Phelan et al.,
2000
; Schnitzler et al.,
1998
). It is unclear as yet
whether these structures correspond to trapped remodeling intermediates or
non-productive `dead-end' molecules. Neither octamer eviction nor stable
structures representing the `remodeled' state have so far been observed during
remodeling by ISWI factors. Apparently, there is more than one mechanism by
which a remodeling ATPase can mobilize a nucleosome.
|
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Perspectives |
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ACKNOWLEDGMENTS |
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---|
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