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Volume 272, Number 44, Issue of October 31, 1997
pp. 27493-27496
From the Laboratory of Receptor Biology and Gene Expression, NCI,
National Institutes of Health, Bethesda, Maryland 20892-5055
INTRODUCTION The past two decades have brought a major
evolution in our understanding of promoter structure, transcription
factors, and mechanisms by which transcriptional initiation is
regulated in eukaryotes. Multiple approaches have been used to
establish current models for transcriptional regulation, including the
development of in vitro transcription systems using either
naked DNA or reconstituted chromatin, genetic analysis of gene
regulation in yeast and Drosophila, and in vivo
analysis of either endogenous cellular genes or transiently transfected, exogenous gene promoters. It is now clear that chromatin structure, once considered to be transparent to the process of transcription, plays an important role in the regulation of gene expression (reviewed in Ref. 1). Since all cellular genes are packaged
into ordered chromatin structures, an understanding of the mechanisms
by which nucleoprotein structure influences transcription activation is
necessary for a complete paradigm of gene regulation in higher
eukaryotes.
Studies on regulation of endogenous mammalian genes are challenging due
to the lack of genetic techniques available in yeast and
Drosophila systems, which allow targeted insertion of
promoters and gene disruption. Structural analysis of integrated gene
promoters in mammalian cells requires the time-consuming generation of
multiple stable cell lines or pools, in which the integrated genes
would be subject to position effects from surrounding chromatin.
Therefore, the identification and characterization of factors involved
in mammalian gene expression have been addressed primarily through the
use of transient transfection assays. In this approach, exogenous plasmid DNA, usually promoter/reporter constructs and transcription factor expression vectors, is introduced into cultured cells and expressed transiently, without replication or integration into the
cellular genome. A variety of transfection methods has been utilized,
including calcium phosphate precipitation (2), DEAE-dextran (3),
electroporation (4, 5), and liposome-mediated transfer (6). These
studies have resulted in an abundance of information about promoter
structure (i.e. identification of cis-acting elements), transcription factor structure and function, and the characterization of transcription factor interactions that are part of various cellular
regulatory pathways. However, in light of the accumulating evidence
indicating a role for chromatin structure in transcription, it is
appropriate to question whether transiently transfected gene promoters
are adequate models for transcriptional regulatory mechanisms active
on endogenous genes in ordered, replicated chromatin.
Structural Studies on Transiently Transfected DNA The first issue to consider for transient templates is whether
these molecules acquire physiologically spaced nucleosomes when
introduced into cultured, mammalian cells. Since assembly of
nucleosomes on endogenous genes is coupled to DNA replication, it is
questionable whether transfected plasmids, which rarely carry mammalian
replication origins, are properly assembled. This issue has not been
extensively studied, but four studies are revealing (7-10). Cereghini
and Yaniv (8) followed the superhelical status of plasmids (transfected
by DEAE-dextran) containing fragments of the SV40 genome with varying
abilities to replicate. Initially, the transfected DNA was in a relaxed
form, but 24 h after transfection it had been converted to
supercoiled forms, indicative of nucleosome formation. In fact,
analysis of micrococcal nuclease digests from transfected cell nuclei
showed the presence of clear, although short, nucleosomal ladders,
whether the transfected DNA had been replicated or not. Repeat lengths
were calculated to be 190 ± 15 bp,1 which is close to that
calculated for bulk cellular chromatin (187 ± 5 bp) (7). In
contrast, Jeong and Stein (7) showed that transfected plasmid DNA
generated anomalous repeat patterns after micrococcal nuclease
digestion. Repeat lengths from their extended ladders were calculated
by more quantitative methodology and found to be 199 ± 5 bp. In
addition, the smallest repeat unit was 280 bp in length, too long to be
a nucleosome monomer and too short to be a nucleosome dimer. This
pattern was found to be reproducible regardless of the cell lines
tested, the size of the plasmid transfected, or the form of the plasmid
transfected (supercoiled versus linear). Unlike bulk
cellular chromatin, the majority of transfected DNA was observed to be
associated with insoluble nuclear material. Although the significance
of this latter observation is unclear, increased repeat lengths would suggest that transfected DNA is generally more open and accessible than
cellular chromatin (Fig.
1B).
[View Larger Version of this Image (46K GIF file)]
Using plasmids transfected by calcium phosphate precipitation, Reeves
et al. (9) showed that nucleosomal ladders could be
generated, which appeared indistinguishable from those of bulk cellular
chromatin. In addition, mononucleosome-sized particles containing
plasmid DNA sequences could be isolated on sucrose gradients after
micrococcal nuclease digestion of transfected cell nuclei. However,
nuclear plasmid DNA was found to exist in an aggregated form, which,
under certain transfection conditions, comprised 80-90% of the total
amount. Also using calcium phosphate precipitation, Archer and
colleagues (10) failed to observe nucleosome repeat patterns on
transiently transfected MMTV promoter constructs under conditions in
which nucleosomal ladders were detectable on stable, replicated forms
of the promoter. Most of the plasmid DNA was completely digested by
micrococcal nuclease, even at the lowest concentrations used. However,
a fraction of the nuclear plasmid DNA was in a form completely
resistant to digestion, even at the highest concentrations used,
possibly representing the aggregated forms of transfected DNA observed
in the previous study. Importantly, the localized nuclease
hypersensitive region induced by the glucocorticoid receptor (GR) at
the MMTV promoter (discussed below) could not be detected on the
transiently introduced promoter construct, indicating that the
chromatin remodeling event associated with activation of the stable,
replicated form of the promoter does not occur on these templates (Fig.
1A). Taken together, the available structural data suggest
that nucleosomes are deposited onto non-replicating DNA in transfected
cells, but the overall structure may be incompletely organized into the
nucleosome arrays characteristic of replicated cellular chromatin.
A major problem in correlating structural features of transfected
templates with function concerns the fraction of the DNA that is
actually transcriptionally active. One way to circumvent this problem
is to examine the binding of transcription factors to the transfected
DNA with the use of a gain-of-signal assay, such as exonuclease
footprinting (11). This assay will detect binding events that occur on
a small fraction of templates, thus permitting an evaluation of
molecular interactions on the active fraction. Archer and colleagues
(10) used this approach to examine binding of factors to the proximal
promoter of the MMTV promoter in a transfected, non-replicating form
versus a stable, replicated form (10). When the replicating
form of the promoter is activated by GR, two factors, NF1 and Oct1,
bind in a hormone-dependent fashion (Fig. 1A)
(12-14). In contrast, these factors are constitutively bound to the
transfected MMTV template, and the amount of their binding does not
increase upon activation of GR (Fig. 1B) (10, 12).
Hormone-dependent binding of the TFIID-basal factor complex on transient templates was observed, indicating that the footprinting assay could detect actual factor-loading events on transcriptionally active templates (12). A reasonable interpretation of these findings is
that transfected DNA does not acquire the repressed chromatin structure
of stable, replicated templates, and this structure is required for
exclusion of ubiquitous factors.
Functional Studies of Transiently Transfected versus Stable
Replicating Templates Evidence of critical structural differences between transiently
transfected DNA and cellular chromatin derives from functional studies
comparing transiently transfected promoters and their stable,
replicating counterparts. In some cases the two templates manifest
similar responses, but there are a growing number of reports showing
significant differences in behavior. Four specific examples will be
briefly mentioned.
1) The 2) Studies on the integrated HIV genome provide another example of
functional differences between transfected and chromosomal templates.
In the ACH-2 and U-1 cell lines, the HIV genome is integrated, but
expression of viral RNA and levels of viral replication are low (19,
20). The activity of a transiently transfected HIV promoter construct
is low in U-1 cells but is constitutively high in ACH-2 cells (20). The
U-1 cells lack functional Tat protein, which is viral encoded and
necessary for viral transcription and replication, because both the
transiently transfected HIV promoter construct and the integrated viral
genome were activated upon addition of exogenous Tat protein. However,
in ACH-2 cells, RNA generated from the integrated genome could not be
increased by addition of exogenous Tat protein, suggesting additional
requirements are necessary for activation from a replicated chromatin
environment (20). The integrated HIV genome in ACH-2 cells was not
defective or irreversibly inactive, since treatment of the cells with
the protein kinase C activator, phorbol 12-myristate 13-acetate,
resulted in increased expression of viral RNA and viral replication
(19, 20).
3) Regulation of the entire human 4) Activation of the c-jun promoter in F9 embryonal
carcinoma cells by retinoic acid treatment or expression of the
adenovirus early 1A (E1A) protein (necessary for adenovirus
transcription and replication) presents another interesting example of
functional differences between transiently transfected and integrated
templates. A stable, integrated c-jun/chloramphenicol
acetyltransferase construct is activated at least 50-fold under these
conditions, whereas the same construct, when transiently transfected,
is activated only 2-3-fold (27). Remarkably, the weak activation of
the latter is dependent on a
12-O-tetradecanoylphorbol-13-acetate response element (28),
but strong activation of the former is dependent on different elements,
a series of direct and inverted repeats (27). Interestingly, some of
these sequences are bound in a retinoic acid- and
E1A-dependent fashion by a complex containing p300 (29),
which has recently been found to be a histone acetyltransferase (30).
These results suggest that a repressive chromatin structure at the
c-jun promoter must be remodeled and the transient template does not require or cannot use this activity.
Each of these examples suggests that transiently transfected promoters,
while they may form nucleosomal structures, are not subject to the same
regulatory mechanisms which operate on their integrated counterparts if
those particular mechanisms involve complex chromatin structure. The
nucleosomal arrays deposited on the transfected, non-replicating DNA
are apparently not as repressive as those formed by
replication-dependent chromatin assembly on endogenous
genes. The functional data indicate that transfected plasmids have a
conformation that simulates the structure of actively transcribing,
derepressed chromosomal genes.
The MMTV Model The MMTV promoter is well characterized in terms of the
nucleoprotein structure it adopts when it is stably replicating, either in an episomal or integrated form (Fig. 1A) (31-34). The
primary feature of this organization is an array of non-randomly
positioned nucleosomes over the regulatory region in the proviral long
terminal repeat (LTR). This structure was originally characterized as a periodic array of micrococcal nuclease and methyldiumpropyl-EDTA-Fe(II) cleavage-sensitive internucleosomal linker regions (35). More recently,
using an in vivo cross-linking procedure for determining nucleosome core positions, Fragoso et al. (33, 37) concluded that the periodic array does not represent precisely positioned nucleosomes but rather consists of a series of nucleosome families (Fig. 1A, A-F) (33). Each family contains a
group of nucleosomes in a frequency-biased distribution among a set of
available translational frames. These findings were reinforced by the
observation that nucleosomes reconstituted in vitro on short
fragments of LTR DNA demonstrated both translational and rotational
complexity (38). An alternate view (34) is that each position
represents a single core, with a unique translational and rotational
position. This interpretation derives primarily from the observation of
10-bp ladders over the B region when lightly digested with DNase I
in vivo. Roberts et al. (38) observed clear 10-bp
periodicities for an in vitro reconstitute that contained
five different core positions, demonstrating the difficulty of using
this criterion for determination of high resolution positions. Similar
data from several other systems (summarized in Fragoso et
al. (33)) is also consistent with multiply positioned cores within
families. Thus, the preponderance of evidence at this time would argue
that even in highly organized and reproducible systems, such as the MMTV LTR, considerable complexity exists in nucleosome positioning.
When steroid receptors interact with the LTR positioned array, a
specific chromatin transition occurs (Fig. 1A) (33, 35). Sequences associated with the B nucleosome family and the 3 Identifying Chromatin-specific Regulatory Mechanisms by Template
Comparison A greater understanding of the role chromatin structure plays in
the regulation of the MMTV promoter has been gained through the
systematic use of template comparison assays. Archer et al. (10) proposed a bimodal model for GR-induced activation of the replicating MMTV template. The first step in activation is
derepression, which involves the conversion of a repressive chromatin
state, through a GR-dependent chromatin remodeling event,
to an open configuration, allowing NF1 and Oct1 access to their binding
sites. The second step involves GR-mediated activation of transcription through interactions with the TFIID-basal factor complex. The transfected MMTV template does not undergo the derepression step because its structure is not repressive to transcription factor binding. Activation of this template most likely involves GR-induced interactions between soluble transcription factors and the basal transcription complex. Functional differences between the transiently transfected and replicating forms of the MMTV promoter may be due to
chromatin-specific events given their different nucleoprotein structures and mechanisms of activation. This approach has been especially fruitful in terms of identifying chromatin-specific events
at the replicating promoter, not only in the depression step but also
in the activation step.
Three lines of investigation indicate a strong role for chromatin in
regulation of MMTV. The first concerns the kinetics of activation.
GR-induced transcription of the replicated template is temporary,
peaking 1 h after addition of hormone and declining to near basal
levels by 24 h, even in the continued presence of steroid (12,
44). This decrease in transcription correlates with a reformation of
the repressed chromatin structure at the promoter (44). In contrast,
the transient template is active as long as glucocorticoids are present
and is not refractory to reactivation if the steroid is removed
(12).
The two MMTV templates also differ dramatically in their response to
progestins. Both GR and the progesterone receptor (PR) bind to the same
hormone response elements in the MMTV promoter (45). However, when the
PR is transiently expressed, it is a poor activator of the replicating
template but efficiently activates the transfected template (Fig.
1C) (44, 46). In contrast, whether transiently or
constitutively expressed, the GR is an efficient activator of both
templates (47). The two receptors also differ in their ability to
induce the chromatin remodeling event at the replicating template;
transiently expressed PR is unable to induce this structural transition
(47). Since the transient template does not require remodeling, the PR
is able to induce its transcription efficiently. These results show
that activation of the replicating template has additional requirements beyond those necessary for activation of the transient template. In
addition, the GR and PR have different requirements for remodeling of
ordered chromatin; this differential may provide a possible mechanism
for achieving selective gene activation in vivo.
The most striking difference in function between the two MMTV templates
occurs in response to cAMP signaling. Whereas the transient template is
synergistically activated by both glucocorticoids and cAMP, the
replicating template is significantly repressed by cAMP in a
glucocorticoid-independent fashion (14). In this case, differences
in the nucleoprotein status of the promoter result in entirely
different modes of regulation. Interestingly, cAMP-induced repression
does not inhibit the GR-induced remodeling event at nucleosome B but
results from inhibition in binding of Oct1 and the TFIID-basal factor
complex to sequences just upstream of the A nucleosome region (Fig.
1D) (14). This observation strongly suggests that, in
addition to the derepression step, there are chromatin-sensitive events
in the second step of the bimodal mechanism by which transcription is
activated at the MMTV template in ordered chromatin. These experimental
findings illustrate the usefulness of the two-template approach for the
identification of pathways in which chromatin participates in the
regulation of transcription.
Template comparison assays have not been limited to the MMTV promoter.
Gerber et al. (36) employed this method to explore differentiation-induced activation of endogenous muscle-specific genes
by MyoD and myogenin. Whereas both proteins activate transiently transfected templates, MyoD was better able to activate genomic copies
of muscle-specific target genes. In fact, expression of MyoD correlated
well with loosening of chromatin structure within the promoters of
these genes. The template comparison assay was also used to identify
domains of MyoD, which are necessary for chromatin remodeling but had
not been associated with any known activation function. Accordingly,
deletion of these regions led to very mild effects on activation of
transfected templates.
Summary The study of mammalian gene expression through the use of
transient transfection assays has greatly expanded our knowledge of
transcriptional mechanisms. However, transfected promoter constructs do
not always serve as appropriate "stand-ins" for endogenous genes,
particularly in cases where chromatin remodeling must take place. The
examples described above indicate that a level of caution is advised
when studying regulation of various promoters and transcription factor
function with the use of transient transfection assays. When possible,
function of the corresponding endogenous promoters should be tested to
assess the validity of regulatory mechanisms defined on transiently
transfected, non-replicating templates. Future studies using template
comparison as a tool will undoubtedly identify which transcription
factors are critical in initiating essential changes in chromatin
structure at endogenous target genes and assist in the elucidation of
mechanisms involved in chromatin transitions. As in the MyoD
experiments (36), these studies will also allow identification of
functional domains in these factors, which are necessary for chromatin
remodeling. Functional differences between transiently transfected and
stable replicating templates need not be considered artifactual but
rather can be exploited to identify and characterize regulatory
mechanisms that involve chromatin components. Full understanding of
gene expression in vivo will not be achieved until these
mechanisms are understood in detail.
FOOTNOTES REFERENCES
MINIREVIEW:
Transcriptional Regulation of Mammalian Genes in
Vivo
A TALE OF TWO TEMPLATES*
INTRODUCTION
Structural Studies on Transiently Transfected DNA
Functional Studies of Transiently Transfected versus Stable
Replicating Templates
The MMTV Model
Identifying Chromatin-specific Regulatory Mechanisms by Template
Comparison
Summary
FOOTNOTES
REFERENCES
Fig. 1.
Chromatin-specific gene regulation.
A, the MMTV LTR acquires a series of nucleosome families
when replicated in mammalian cells; for simplicity, each family is
depicted here as a single nucleosome. Steroid receptors bind to the B
nucleosome region and induce chromatin remodeling (step 1).
This transition leads to binding of constitutive factors that are
excluded from unremodeled chromatin. H1 is also lost from the local
chromatin domain. Newly bound factors interact with the basal complex
by protein-protein interactions (step 2). Dex,
dexamethasone. B, LTR sequences introduced transiently into
cultured cells become associated with histones but do not acquire
highly organized and correctly positioned nucleosomes. C,
the transiently expressed progesterone receptor cannot remodel MMTV
chromatin effectively (blocked in step 1) but activates
disorganized templates. D, coactivation of the
glucocorticoid receptor and the protein kinase A (PKA)
pathway leads to a dominant phosphorylation event specific to chromatin
templates; B region remodeling (step 1) is normal, but basal
complex loading on organized nucleoprotein templates is repressed
(step 2).
1-antitrypsin gene is actively transcribed in
hepatocytes, but its expression is extinguished upon fusion of cultured hepatocytes with fibroblasts. Transiently transfected promoter constructs respond primarily to the activator, HNF-1 (15, 16); expression of this activator is also extinguished upon fusion (17, 18).
Ectopic expression of HNF-1 results in activation of the transient
promoter template in fibroblasts and hepatocyte/fibroblast fusions
(15). However, the endogenous 1-antitrypsin gene cannot be activated in either of these circumstances, and its
fusion-dependent extinction cannot be prevented by
constitutively expressed HNF-1 (15), indicating that the regulation of
the endogenous promoter is more complex than indicated by studies with
the transfected version.
-globin gene genomic locus is
controlled by a large region containing four erythroid-specific DNase
I-hypersensitive sites (HS) (21, 22), referred to collectively as the
locus control region. Examination of each hypersensitive region through
transient transfection revealed that only the HS2 region had classical
enhancer activity or the ability to activate a minimal promoter from a
distance in an orientation-dependent fashion (23). In
contrast, all four regions are required for full, copy
number-dependent, position-independent expression in transgenic animals (24, 25). The HS2 region by itself is ineffective in
allowing activation of single copy transgenes (25, 26). Only through
examination of stable replicating forms of the -globin gene was it
determined that HS3 contains chromatin opening activity (25).
-edge of
the C family become hypersensitive to attack by DNase I,
methyldiumpropyl-EDTA-Fe(II), and restriction endonucleases. This
transition is notably not associated with the A nucleosome
region, where transcription initiation takes place. Histone H1 is also
lost from the local chromatin domain (39) in a
receptor-dependent fashion. This remodeling event leads to
binding by secondary proteins, NF1 and Oct1, which are present in the
nucleus but apparently unable to bind to the unremodeled MMTV LTR
because of its chromatin structure (10, 13). The nature of this
remodeling event is now the subject of considerable research activity,
given its central role in gene activation. Two basic issues of
immediate interest include the identification of activities required
for the transition, in addition to the receptor itself, and
characterization of the molecular nature of the transition. Required
remodeling cofactors may include nucleosome remodeling activities such
as the SWI/SNF (40) or NURF (41) complexes or histone
acetyltransferases (30, 42). Current models for chromatin remodeling
focus on reorganization of the nucleosome core components. Remodeling
by the SWI/SNF complex has been argued to involve loss of H2A/H2B
dimers from associated octamer cores in vitro (43). However,
there is very little direct in vivo evidence on the nature
of the chromatin remodeling event. Fragoso et al. (33)
failed to detect significant loss of histone/DNA cross-links in the
MMTV B nucleosome region transition, but these studies need to be
extended to higher resolution and sensitivity. Finally, it is probably
shortsighted to think in terms of remodeling processes only at the
level of the nucleosome core. Changes in higher order relationships
between nucleosome/chromatin components may be triggered by receptor
binding (e.g. histone H1 is displaced), and these
rearrangements may be important in altering accessibility of soluble
factors to the nucleoprotein template. Small, transiently transfected
templates are not likely to acquire these higher order levels of
chromatin structure.
To whom correspondence should be addressed: Laboratory of Receptor
Biology and Gene Expression, Bldg. 41, Rm. B602, NCI, NIH, Bethesda, MD
20892-5055. E-mail: hagerg{at}dce41.nci.nih.gov.
1
The abbreviations used are: bp, base pair(s);
MMTV, murine mammary tumor virus; GR, glucocorticoid receptor; HIV,
human immunodeficiency virus; HS, hypersensitive site; LTR, long
terminal repeat; PR, progesterone receptor.
Volume 272, Number 44,
Issue of October 31, 1997
pp. 27493-27496
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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 C. Frigeri, C. C. Martin, C. A. Svitek, J. K. Oeser, J. C. Hutton, M. Gannon, and R. M. O'Brien The Proximal Islet-Specific Glucose-6-Phosphatase Catalytic Subunit-Related Protein Autoantigen Promoter Is Sufficient to Initiate but not Maintain Transgene Expression in Mouse Islets in Vivo Diabetes, July 1, 2004; 53(7): 1754 - 1764. [Abstract] [Full Text] [PDF]
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D. U. Lee, O. Avni, L. Chen, and A. Rao A Distal Enhancer in the Interferon-{gamma} (IFN-{gamma}) Locus Revealed by Genome Sequence Comparison J. Biol. Chem., February 6, 2004; 279(6): 4802 - 4810. [Abstract] [Full Text] [PDF]
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J. Lu, M. J. Pazin, and K. Ravid Properties of Ets-1 Binding to Chromatin and Its Effect on Platelet Factor 4 Gene Expression Mol. Cell. Biol., January 1, 2004; 24(1): 428 - 441. [Abstract] [Full Text] [PDF]
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J. Mamet, M. Lazdunski, and N. Voilley How Nerve Growth Factor Drives Physiological and Inflammatory Expressions of Acid-sensing Ion Channel 3 in Sensory Neurons J. Biol. Chem., December 5, 2003; 278(49): 48907 - 48913. [Abstract] [Full Text] [PDF]
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 D. L. Popkin, M. A. Watson, E. Karaskov, G. P. Dunn, R. Bremner, and H. W. Virgin IV Murine cytomegalovirus paralyzes macrophages by blocking IFN{gamma}-induced promoter assembly PNAS, November 25, 2003; 100(24): 14309 - 14314. [Abstract] [Full Text] [PDF]
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T. Senawong, V. J. Peterson, D. Avram, D. M. Shepherd, R. A. Frye, S. Minucci, and M. Leid Involvement of the Histone Deacetylase SIRT1 in Chicken Ovalbumin Upstream Promoter Transcription Factor (COUP-TF)-interacting Protein 2-mediated Transcriptional Repression J. Biol. Chem., October 31, 2003; 278(44): 43041 - 43050. [Abstract] [Full Text] [PDF]
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G. Kennedy and B. Sugden EBNA-1, a Bifunctional Transcriptional Activator Mol. Cell. Biol., October 1, 2003; 23(19): 6901 - 6908. [Abstract] [Full Text] [PDF]
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 L. C. Olds and E. Sibley Lactase persistence DNA variant enhances lactase promoter activity in vitro: functional role as a cis regulatory element Hum. Mol. Genet., September 15, 2003; 12(18): 2333 - 2340. [Abstract] [Full Text] [PDF]
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N. Gao, J. Zhang, M. A. Rao, T. C. Case, J. Mirosevich, Y. Wang, R. Jin, A. Gupta, P. S. Rennie, and R. J. Matusik The Role of Hepatocyte Nuclear Factor-3{alpha} (Forkhead Box A1) and Androgen Receptor in Transcriptional Regulation of Prostatic Genes Mol. Endocrinol., August 1, 2003; 17(8): 1484 - 1507. [Abstract] [Full Text] [PDF]
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P. T. Georgel, T. M. Fletcher, G. L. Hager, and J. C. Hansen Formation of higher-order secondary and tertiary chromatin structures by genomic mouse mammary tumor virus promoters Genes & Dev., July 1, 2003; 17(13): 1617 - 1629. [Abstract] [Full Text] [PDF]
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J. R. Lambert and S. K. Nordeen CBP Recruitment and Histone Acetylation in Differential Gene Induction by Glucocorticoids and Progestins Mol. Endocrinol., June 1, 2003; 17(6): 1085 - 1094. [Abstract] [Full Text] [PDF]
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 C. Rodriguez-Antona, R. Bort, R. Jover, N. Tindberg, M. Ingelman-Sundberg, M. J. Gomez-Lechon, and J. V. Castell Transcriptional Regulation of Human CYP3A4 Basal Expression by CCAAT Enhancer-Binding Protein alpha and Hepatocyte Nuclear Factor-3gamma Mol. Pharmacol., May 1, 2003; 63(5): 1180 - 1189. [Abstract] [Full Text] [PDF]
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Q. Lu, A. E. Hutchins, C. M. Doyle, J. R. Lundblad, and R. P. S. Kwok Acetylation of cAMP-responsive Element-binding Protein (CREB) by CREB-binding Protein Enhances CREB-dependent Transcription J. Biol. Chem., April 25, 2003; 278(18): 15727 - 15734. [Abstract] [Full Text] [PDF]
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S.-Y. Kim, M.-S. Woo, W.-K. Kim, E.-C. Choi, J. W. Henson, and H.-S. Kim Glial Cell-Specific Regulation of the JC Virus Early Promoter by Histone Deacetylase Inhibitors J. Virol., March 15, 2003; 77(6): 3394 - 3401. [Abstract] [Full Text] [PDF]
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S. Kuo, A. L. Chokas, R. J. Rogers, and H. S. Nick PIN*POINT analysis on the endogenous MnSOD promoter: specific demonstration of Sp1 binding in vivo Am J Physiol Cell Physiol, February 1, 2003; 284(2): C528 - C534. [Abstract] [Full Text] [PDF]
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C. Hernandez-Munain and M. S. Krangel Distinct Roles for c-Myb and Core Binding Factor/Polyoma Enhancer-Binding Protein 2 in the Assembly and Function of a Multiprotein Complex on the TCR {delta} Enhancer In Vivo J. Immunol., October 15, 2002; 169(8): 4362 - 4369. [Abstract] [Full Text] [PDF]
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M. Yaekashiwa and L.-H. Wang Transcriptional Control of the Human Thromboxane Synthase Gene in Vivo and in Vitro J. Biol. Chem., June 14, 2002; 277(25): 22497 - 22508. [Abstract] [Full Text] [PDF]
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Y.-H. Lee, S. S. Koh, X. Zhang, X. Cheng, and M. R. Stallcup Synergy among Nuclear Receptor Coactivators: Selective Requirement for Protein Methyltransferase and Acetyltransferase Activities Mol. Cell. Biol., June 1, 2002; 22(11): 3621 - 3632. [Abstract] [Full Text] [PDF]
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E. Soeth, D. B. Thurber, and C. L. Smith The Viral Transactivator E1A Regulates the Mouse Mammary Tumor Virus Promoter in an Isoform- and Chromatin-specific Manner J. Biol. Chem., May 24, 2002; 277(22): 19847 - 19854. [Abstract] [Full Text] [PDF]
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Y. Liang, X.-Y. Li, E. J. Rebar, P. Li, Y. Zhou, B. Chen, A. P. Wolffe, and C. C. Case Activation of Vascular Endothelial Growth Factor A Transcription in Tumorigenic Glioblastoma Cell Lines by an Enhancer with Cell Type-specific DNase I Accessibility J. Biol. Chem., May 24, 2002; 277(22): 20087 - 20094. [Abstract] [Full Text] [PDF]
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T. M. Fletcher, N. Xiao, G. Mautino, C. T. Baumann, R. Wolford, B. S. Warren, and G. L. Hager ATP-Dependent Mobilization of the Glucocorticoid Receptor during Chromatin Remodeling Mol. Cell. Biol., May 15, 2002; 22(10): 3255 - 3263. [Abstract] [Full Text] [PDF]
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 P. Qiu and L. Li Histone Acetylation and Recruitment of Serum Responsive Factor and CREB-Binding Protein Onto SM22 Promoter During SM22 Gene Expression Circ. Res., May 3, 2002; 90(8): 858 - 865. [Abstract] [Full Text] [PDF]
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A. R. Nawrocki, C. E. Goldring, R. M. Kostadinova, F. J. Frey, and B. M. Frey In Vivo Footprinting of the Human 11beta -Hydroxysteroid Dehydrogenase Type 2 Promoter. EVIDENCE FOR CELL-SPECIFIC REGULATION BY Sp1 AND Sp3 J. Biol. Chem., April 19, 2002; 277(17): 14647 - 14656. [Abstract] [Full Text] [PDF]
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 G. K. Scott, C. Marden, F. Xu, L. Kirk, and C. C. Benz Transcriptional Repression of ErbB2 by Histone Deacetylase Inhibitors Detected by a Genomically Integrated ErbB2 Promoter-reporting Cell Screen Mol. Cancer Ther., April 1, 2002; 1(6): 385 - 392. [Abstract] [Full Text] [PDF]
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B. Lefebvre, C. Brand, P. Lefebvre, and K. Ozato Chromosomal Integration of Retinoic Acid Response Elements Prevents Cooperative Transcriptional Activation by Retinoic Acid Receptor and Retinoid X Receptor Mol. Cell. Biol., March 1, 2002; 22(5): 1446 - 1459. [Abstract] [Full Text] [PDF]
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 J. A. Mengshol, M. P. Vincenti, and C. E. Brinckerhoff IL-1 induces collagenase-3 (MMP-13) promoter activity in stably transfected chondrocytic cells: requirement for Runx-2 and activation by p38 MAPK and JNK pathways Nucleic Acids Res., November 1, 2001; 29(21): 4361 - 4372. [Abstract] [Full Text] [PDF]
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B. P. Ashburner, S. D. Westerheide, and A. S. Baldwin Jr. The p65 (RelA) Subunit of NF-{kappa}B Interacts with the Histone Deacetylase (HDAC) Corepressors HDAC1 and HDAC2 To Negatively Regulate Gene Expression Mol. Cell. Biol., October 15, 2001; 21(20): 7065 - 7077. [Abstract] [Full Text] [PDF]
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I. Manabe and G. K. Owens The Smooth Muscle Myosin Heavy Chain Gene Exhibits Smooth Muscle Subtype-selective Modular Regulation in Vivo J. Biol. Chem., October 12, 2001; 276(42): 39076 - 39087. [Abstract] [Full Text] [PDF]
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D. L. Stenoien, A. C. Nye, M. G. Mancini, K. Patel, M. Dutertre, B. W. O'Malley, C. L. Smith, A. S. Belmont, and M. A. Mancini Ligand-Mediated Assembly and Real-Time Cellular Dynamics of Estrogen Receptor {alpha}-Coactivator Complexes in Living Cells Mol. Cell. Biol., July 1, 2001; 21(13): 4404 - 4412. [Abstract] [Full Text] [PDF]
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E. Shestakova, M.-T. Bandu, J. Doly, and E. Bonnefoy Inhibition of Histone Deacetylation Induces Constitutive Derepression of the Beta Interferon Promoter and Confers Antiviral Activity J. Virol., April 1, 2001; 75(7): 3444 - 3452. [Abstract] [Full Text]
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F. D. Urnov and A. P. Wolffe A Necessary Good: Nuclear Hormone Receptors and Their Chromatin Templates Mol. Endocrinol., January 1, 2001; 15(1): 1 - 16. [Full Text]
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E. S. Lymar, A. M. Clark, R. Reeves, and M. D. Griswold Clusterin Gene in Rat Sertoli Cells Is Regulated by a Core-Enhancer Element Biol Reprod, November 1, 2000; 63(5): 1341 - 1351. [Abstract] [Full Text]
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T. M. Fletcher, B.-W. Ryu, C. T. Baumann, B. S. Warren, G. Fragoso, S. John, and G. L. Hager Structure and Dynamic Properties of a Glucocorticoid Receptor-Induced Chromatin Transition Mol. Cell. Biol., September 1, 2000; 20(17): 6466 - 6475. [Abstract] [Full Text]
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S. Suzuki-Ishigaki, K. Numayama-Tsuruta, A. Kuramasu, E. Sakurai, Y. Makabe, S. Shimura, K. Shirato, K. Igarashi, T. Watanabe, and H. Ohtsu The mouse L-histidine decarboxylase gene: structure and transcriptional regulation by CpG methylation in the promoter region Nucleic Acids Res., July 15, 2000; 28(14): 2627 - 2633. [Abstract] [Full Text] [PDF]
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G. Verrijdt, E. Schoenmakers, A. Haelens, B. Peeters, G. Verhoeven, W. Rombauts, and F. Claessens Change of Specificity Mutations in Androgen-selective Enhancers. EVIDENCE FOR A ROLE OF DIFFERENTIAL DNA BINDING BY THE ANDROGEN RECEPTOR J. Biol. Chem., April 14, 2000; 275(16): 12298 - 12305. [Abstract] [Full Text] [PDF]
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J. S. Kang and J.-S. Kim Zinc Finger Proteins as Designer Transcription Factors J. Biol. Chem., March 17, 2000; 275(12): 8742 - 8748. [Abstract] [Full Text] [PDF]
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L. F. Michael, H. Asahara, A. I. Shulman, W. L. Kraus, and M. Montminy The Phosphorylation Status of a Cyclic AMP-Responsive Activator Is Modulated via a Chromatin-Dependent Mechanism Mol. Cell. Biol., March 1, 2000; 20(5): 1596 - 1603. [Abstract] [Full Text]
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 J. G. McNally, W. G. Müller, D. Walker, R. Wolford, and G. L. Hager The Glucocorticoid Receptor: Rapid Exchange with Regulatory Sites in Living Cells Science, February 18, 2000; 287(5456): 1262 - 1265. [Abstract] [Full Text]
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H. D. Brightbill, S. E. Plevy, R. L. Modlin, and S. T. Smale A Prominent Role for Sp1 During Lipopolysaccharide- Mediated Induction of the IL-10 Promoter in Macrophages J. Immunol., February 15, 2000; 164(4): 1940 - 1951. [Abstract] [Full Text] [PDF]
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M. C. Lorincz, D. Schübeler, S. C. Goeke, M. Walters, M. Groudine, and D. I. K. Martin Dynamic Analysis of Proviral Induction and De Novo Methylation: Implications for a Histone Deacetylase-Independent, Methylation Density-Dependent Mechanism of Transcriptional Repression Mol. Cell. Biol., February 1, 2000; 20(3): 842 - 850. [Abstract] [Full Text]
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 E Genersch, K Hayess, Y Neuenfeld, and H Haller Sustained ERK phosphorylation is necessary but not sufficient for MMP-9 regulation in endothelial cells: involvement of Ras-dependent and -independent pathways J. Cell Sci., January 12, 2000; 113(23): 4319 - 4330. [Abstract] [PDF]
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J. D. Furlow and D. D. Brown In Vitro and in Vivo Analysis of the Regulation of a Transcription Factor Gene by Thyroid Hormone during Xenopus laevis Metamorphosis Mol. Endocrinol., December 1, 1999; 13(12): 2076 - 2089. [Abstract] [Full Text]
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A. Javed, S. Gutierrez, M. Montecino, A. J. van Wijnen, J. L. Stein, G. S. Stein, and J. B. Lian Multiple Cbfa/AML Sites in the Rat Osteocalcin Promoter Are Required for Basal and Vitamin D-Responsive Transcription and Contribute to Chromatin Organization Mol. Cell. Biol., November 1, 1999; 19(11): 7491 - 7500. [Abstract] [Full Text] [PDF]
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A. J. Crowe, L. Sang, K. K. Li, K. C. Lee, B. T. Spear, and M. C. Barton Hepatocyte Nuclear Factor 3 Relieves Chromatin-mediated Repression of the alpha -Fetoprotein Gene J. Biol. Chem., August 27, 1999; 274(35): 25113 - 25120. [Abstract] [Full Text] [PDF]
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E. Bonnefoy, M.-T. Bandu, and J. Doly Specific Binding of High-Mobility-Group I (HMGI) Protein and Histone H1 to the Upstream AT-Rich Region of the Murine Beta Interferon Promoter: HMGI Protein Acts as a Potential Antirepressor of the Promoter Mol. Cell. Biol., April 1, 1999; 19(4): 2803 - 2816. [Abstract] [Full Text] [PDF]
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C. S. Lim, C. T. Baumann, H. Htun, W. Xian, M. Irie, C. L. Smith, and G. L. Hager Differential Localization and Activity of the A- and B-Forms of the Human Progesterone Receptor Using Green Fluorescent Protein Chimeras Mol. Endocrinol., March 1, 1999; 13(3): 366 - 375. [Abstract] [Full Text]
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M. J. Pazin, J. W. Hermann, and J. T. Kadonaga Promoter Structure and Transcriptional Activation with Chromatin Templates Assembled In Vitro. A SINGLE Gal4-VP16 DIMER BINDS TO CHROMATIN OR TO DNA WITH COMPARABLE AFFINITY J. Biol. Chem., December 18, 1998; 273(51): 34653 - 34660. [Abstract] [Full Text] [PDF]
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A. Krumm, L. Madisen, X.-J. Yang, R. Goodman, Y. Nakatani, and M. Groudine Long-distance transcriptional enhancement by the histone acetyltransferase PCAF PNAS, November 10, 1998; 95(23): 13501 - 13506. [Abstract] [Full Text] [PDF]
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M. Tsai-Pflugfelder, S. M. Gasser, and W. Wahli Functional Interaction between the Estrogen Receptor and CTF1: Analysis of the Vitellogenin Gene B1 Promoter in Yeast Mol. Endocrinol., October 1, 1998; 12(10): 1525 - 1541. [Abstract] [Full Text]
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W. Zhang and J. J. Bieker Acetylation and modulation of erythroid Kruppel-like factor (EKLF) activity by interaction with histone acetyltransferases PNAS, August 18, 1998; 95(17): 9855 - 9860. [Abstract] [Full Text] [PDF]
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F. Uchiumi, T. Sato, and S.-i. Tanuma Identification and Characterization of a Tannic Acid-responsive Negative Regulatory Element in the Mouse Mammary Tumor Virus Promoter J. Biol. Chem., May 15, 1998; 273(20): 12499 - 12508. [Abstract] [Full Text] [PDF]
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J. Pan, L. Xia, and R. P. McEver Comparison of Promoters for the Murine and Human P-selectin Genes Suggests Species-specific and Conserved Mechanisms for Transcriptional Regulation in Endothelial Cells J. Biol. Chem., April 17, 1998; 273(16): 10058 - 10067. [Abstract] [Full Text] [PDF]
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W. Ma, W. Lim, K. Gee, S. Aucoin, D. Nandan, M. Kozlowski, F. Diaz-Mitoma, and A. Kumar The p38 Mitogen-activated Kinase Pathway Regulates the Human Interleukin-10 Promoter via the Activation of Sp1 Transcription Factor in Lipopolysaccharide-stimulated Human Macrophages J. Biol. Chem., April 20, 2001; 276(17): 13664 - 13674. [Abstract] [Full Text] [PDF]
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F. D. Urnov and A. P. Wolffe An Array of Positioned Nucleosomes Potentiates Thyroid Hormone Receptor Action in Vivo J. Biol. Chem., June 1, 2001; 276(23): 19753 - 19761. [Abstract] [Full Text] [PDF]
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N. Cervoni and M. Szyf Demethylase Activity Is Directed by Histone Acetylation J. Biol. Chem., October 26, 2001; 276(44): 40778 - 40787. [Abstract] [Full Text] [PDF]
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P. Qiu and L. Li Histone Acetylation and Recruitment of Serum Responsive Factor and CREB-Binding Protein Onto SM22 Promoter During SM22 Gene Expression Circ. Res., May 3, 2002; 90(8): 858 - 865. [Abstract] [Full Text] [PDF]
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