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23 CONTROLLING CHROMATIN STRUCTURE (Full Edition)
4 Nucleosome organization may be changed at the promoter
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Remodeling complexes are recruited to promoters by sequence-specific activators.
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The factor may be released once the remodeling complex has bound.
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The
MMTV promoter requires a change in rotational positioning of a
nucleosome to allow an activator to bind to DNA on the nucleosome.
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Figure 23.6
A remodeling complex binds to chromatin via an activator (or repressor).
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How are remodeling complexes targeted to
specific sites on chromatin? They do not themselves contain subunits
that bind specific DNA sequences. This suggests the model shown in Figure 23.6
in which they are recruited by activators or (sometimes) by repressors (1864; 1970).
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The interaction between transcription
factors and remodeling complexes gives a key insight into their modus
operandi. The transcription factor Swi5p activates the HO
locus in yeast. (Note that Swi5p is not a member of the SWI/SNF
complex.) Swi5p enters nuclei toward the end of mitosis and binds to
the HO promoter. It then recruits SWI/SNF to the promoter.
Then Swi5p is released, leaving SWI/SNF at the promoter (1966).
This means that a transcription factor can activate a promoter by a
"hit and run" mechanism, in which its function is fulfilled once the
remodeling complex has bound.
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The involvement of remodeling complexes
in gene activation was discovered because the complexes are necessary
for the ability of certain transcription factors to activate their
target genes. One of the first examples was the GAGA factor, which
activates the hsp70 Drosophila promoter in vitro.
Binding of GAGA to four (CT)n-rich
sites on the promoter disrupts the nucleosomes, creates a
hypersensitive region, and causes the adjacent nucleosomes to be
rearranged so that they occupy preferential instead of random
positions. Disruption is an energy-dependent process that requires the
NURF remodeling complex. The organization of nucleosomes is altered so
as to create a boundary that determines the positions of the adjacent
nucleosomes (691). During this process, GAGA binds to its target
sites and DNA, and its presence fixes the remodeled state.
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The PHO system was one of the
first in which it was shown that a change in nucleosome organization is
involved in gene activation (for review see 1976). At the PHO5
promoter, the bHLH regulator PHO4 responds to phosphate starvation by
inducing the disruption of four precisely positioned nucleosomes. This
event is independent of transcription (it occurs in a TATA
–
mutant) and independent of replication. There are two binding sites for
PHO4 at the promoter, one located between nucleosomes, which can be
bound by the isolated DNA-binding domain of PHO4, and the other within
a nucleosome, which cannot be recognized. Disruption of the nucleosome
to allow DNA binding at the second site is necessary for gene
activation. This action requires the presence of the
transcription-activating domain. The activator sequence of VP16 can
substitute for the PHO4 activator sequence in nucleosome disruption.
This suggests that disruption occurs by protein-protein interactions
that involve the same region that makes protein-protein contacts to
activate transcription (605).
In this case, it is not known which remodeling complex is involved in executing the effects.
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It is not always the case, however, that
nucleosomes must be excluded in order to permit initiation of
transcription. Some activators can bind to DNA on a nucleosomal
surface. Nucleosomes appear to be precisely positioned at some steroid
hormone response elements in such a way that receptors can bind.
Receptor binding may alter the interaction of DNA with histones, and
even lead to exposure of new binding sites. The exact positioning of
nucleosomes could be required either because the nucleosome "presents"
DNA in a particular rotational phase or because there are
protein-protein interactions between the activators and histones or
other components of chromatin. So we have now moved some way from
viewing chromatin exclusively as a repressive structure to considering
which interactions between activators and chromatin can be required for
activation.
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Figure 23.7
Hormone receptor and NF1 cannot bind simultaneously to
the MMTV promoter in the form of linear DNA, but can bind when the DNA
is presented on a nucleosomal surface.
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The MMTV promoter presents an example of
the need for specific nucleosomal organization. It contains an array of
6 partly palindromic sites, each bound by one dimer of hormone receptor
(HR), which constitute the HRE. It also has a single binding site for
the factor NF1, and two adjacent sites for the factor OTF. HR and NF1
cannot bind simultaneously to their sites in free DNA. Figure 23.7 shows
how the nucleosomal structure controls binding of the factors.
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The HR protects its binding sites at the
promoter when hormone is added, but does not affect the micrococcal
nuclease-sensitive sites that mark either side of the nucleosome. This
suggests that HR is binding to the DNA on the nucleosomal surface.
However, the rotational positioning of DNA on the nucleosome prior to
hormone addition allows access to only two of the four sites. Binding
to the other two sites requires a change in rotational positioning on
the nucleosome. This can be detected by the appearance of a sensitive
site at the axis of dyad symmetry (which is in the center of the
binding sites that constitute the HRE). NF1 can be footprinted on the
nucleosome after hormone induction, so these structural changes may be
necessary to allow NF1 to bind, perhaps because they expose DNA and
abolish the steric hindrance by which HR blocks NF1 binding to free DNA
(687; 690).
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Last Revised on 9-5-2001
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1976 Lohr, D.
(1997).
Nucleosome transactions on the promoters of the yeast GAL and PHO genes.
J. Biol. Chem. 272, 26795-26798.
PubMed Journal
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605 Schmid, V. M., Fascher, K.-D., and Horz, W.
(1992).
Nucleosome disruption at the yeast PHO5 promoter upon PHO5 induction occurs in the absence of DNA replication.
Cell 71, 853-864.
PubMed Journal
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687 McPherson, C. E., Shim, E.-Y., Friedman, D.
S., and Zaret, K. S. (1993). An active tissue-specific enhancer
and bound transcription factors existing in a precisely positioned
nucleosomal array. Cell 75, 387-398. PubMed Journal
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690 Truss, M., Barstch, J., Schelbert, A., Hache, R. J. G., and Beato, M.
(1994).
Hormone induces binding of receptors and transcription factors to a rearranged nucleosome on the MMTV promoter in vitro.
EMBO J. 14, 1737-1751.
PubMed
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691 Tsukiyama, T., Becker, P. B., and Wu, C.
(1994).
ATP-dependent nucleosome disruption at a heat shock promoter mediated by binding of GAGA transcription factor.
Nature 367, 525-532.
PubMed Journal
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1864 Kadam, S., McAlpine, G. S., Phelan, M. L., Kingston, R. E., Jones, K. A., and Emerson, B. M.
(2000).
Functional selectivity of recombinant mammalian SWI/SNF subunits.
Genes Dev. 14, 2441-2451.
PubMed Journal
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1966 Cosma, M. P., Tanaka, T., and Nasmyth, K.
(1999). Ordered recruitment of transcription and chromatin
remodeling factors to a cell cycle- and developmentally regulated
promoter. Cell 97, 299-311. PubMed Journal
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1970 Yudkovsky, N., Logie, C., Hahn, S., and Peterson, C. L.
(1999).
Recruitment of the SWI/SNF chromatin remodeling complex by transcriptional activators.
Genes Dev. 13, 2369-2374.
PubMed Journal
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©Jones and Bartlett Publishers (2007)
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