(Hypertension. 1996;27:1025-1029.)
© 1996 American Heart Association, Inc.
Articles |
Mechanisms of Transcriptional Synergism of Eukaryotic Genes
The Interferon-ß Paradigm
From the Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY.
Correspondence to Dimitris Thanos, Department of Biochemistry and Molecular Biophysics, Columbia University, 630 W 168th St, New York, NY 10032.
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Abstract |
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 Top Abstract IntroductionThe IFN SystemOrganization of the Human...IFN-ß Gene Transcriptional...The Mechanism of Combinatorial...References |
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Abstract The virus-inducible enhancer of the human interferon-ß gene has served as an excellent example for the mechanisms controlling the activation and repression of transcription. This enhancer is activated by three different transcription factors that, with the help of the high mobility group protein HMG I(Y), assemble in a unique nucleoprotein complex that interacts as a unit with the basal transcriptional machinery. The assembly of unique enhancer complexes from similar sets of transcription factors may provide the specificity required for regulation of complex patterns of gene expression in higher eukaryotes.
Key Words: transcription, genetic • genes, eukaryotic • interferon-beta
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Introduction |
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TopAbstractIntroductionThe IFN SystemOrganization of the Human...IFN-ß Gene Transcriptional...The Mechanism of Combinatorial...References |
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Regulation of gene expression in eukaryotic organisms plays a pivotal role in the development and differentiation of functionally distinct cell types in a precise spatial manner. The expression of some genes in a cell- or tissue-specific manner is responsible for cell identity and morphological or functional specialization, whereas other genes are turned on constitutively in all cell types and are responsible for cell homeostasis (housekeeping genes). In contrast, a plethora of genes is specifically expressed only in response to extracellular signals such as growth factors, cytokines, hormones, heat shock, and virus infection. Since regulation of gene expression is mainly achieved by alterations in the rate of mRNA synthesis, it appears that eukaryotic genes are mostly regulated at the transcriptional level. Central players in these pathways are sequence-specific DNA binding proteins that recognize short cis-regulatory motifs present in the promoters and enhancers of all eukaryotic genes. Some transcriptional activators, such as the members of the MyoD family, have the remarkable property to convert a large number of different cell types into muscle.1 Thus, in this case, cell identity is specified during development by the presence of these proteins in the appropriate progenitor cells.
Although tissue-specific transcriptional activation is largely due to the presence of one or more particular activators in the appropriate cell type, the mechanism of inducible gene expression is far more complicated. In this case, the transcriptional regulator must sense a signal, such as a hormone, cytokine, or growth factor bound to a receptor, and then adjust transcription of the appropriate genes. Thus, intracellular signal transduction pathways play a critical role in transcriptional activation. Remarkably, recent studies have established that similar pathways are involved in immune function in mammalian cells and in the establishment of the dorsoventral polarity in the developing Drosophila embryo.2 The end points of these pathways regulate the activity of transcription factors at different levels, such as cellular compartmentalization (nuclear versus cytoplasmic), DNA binding, and/or transcriptional activation.3 The property of distinct signal transduction pathways to converge and activate the same transcription factor or the fact that distinct stimuli induce the same pathway raised a fundamental question related to the specificity of the response; that is, how is the action of a transcription factor restricted to the appropriate genes? The solution to this apparent paradox appears to involve combinatorial interactions between the signal transduction pathways, the transcription factors, or both. The response elements of eukaryotic genes usually contain binding sites for multiple regulatory factors that can be activated by distinct or similar signaling pathways. In principle, these elements serve as the junction points where divergent signals can converge to produce novel patterns of expression due to the assembly of unique nucleoprotein complexes.4 Moreover, the selection of a specific member from a multigene family of transcription factors provides an additional level of specificity because each member may be differentially activated or display differential sequence specificity from other members. In this article, I review recent progress in understanding the mechanisms of the activation of gene expression in response to extracellular signals. Specifically, I will use an example to illustrate two distinct but functionally overlapping aspects of specificity in the transcriptional response. I will examine first the mechanism by which a particular signal targets a specific set of transcription factors, and second, the mechanism by which the activated transcription factors target the correct gene. Perhaps one of the best-characterized model systems that culminates all of the above is the IFN system in mammals.
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The IFN System |
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TopAbstractIntroductionThe IFN SystemOrganization of the Human...IFN-ß Gene Transcriptional...The Mechanism of Combinatorial...References |
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The IFNs were discovered in the middle 1950s as biological compounds that increased cellular resistance to virus infection.5 IFNs are a heterogeneous family of secreted polypeptides with multiple biological functions. They are essential components of the host defense mechanism against virus infections but also play a critical role in cell growth and differentiation and in other immunoregulatory biological functions of the higher organisms (reviewed in References 6 and 7). The IFN protein family has been divided into two groups based on differences in their structures, function, and modes of synthesis. The first group includes the IFN-
/ß family, also known as type I IFN, consisting of 20
highly similar IFN- genes and a single IFN-ß gene, all of which
are clustered on chromosome 9 in humans. The second group, type II IFN,
consists of a single gene encoding the IFN-
protein, which is also
known as immune IFN. The type I IFNs (IFN-/ß) are rapidly induced
in almost every cell type after virus infection, and the type II IFN
(IFN-) is produced by activated T lymphocytes and natural
killer cells.6 7
Recently, a combination of biochemical and genetic approaches have shed
light on the molecular mechanisms and signaling pathways involved in
the antiviral response. The first step in the antiviral response
requires transcriptional activation of the type I IFN genes. Before
virus infection, the level of IFN mRNA is undetectable, but within
hours after infection, more than 4000 transcripts per cell are
produced. The synthesized IFN proteins are secreted and bind to
specific cell surface receptors, thereby activating the expression of a
large number of genes encoding antiviral proteins (Fig 1
). Thus, the antiviral response is a two-step
pathway involving the activation of IFNs and of IFN-inducible genes. In
this review, I focus on the transcriptional activation of the human
IFN-ß gene. Over the past 5 years, our knowledge about the second
step of this signaling pathway has been significantly advanced by the
identification and characterization of the components required for
IFN-dependent transcriptional activation (reviewed in Reference 8).
Although little is known about the signal transduction pathway
operating at the first step of this pathway, virus induction of the
IFN-ß gene has provided a useful model system for study of the
mechanisms involved in gene induction and repression.
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Organization of the Human IFN-ß Gene Regulatory Elements |
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TopAbstractIntroductionThe IFN SystemOrganization of the Human...IFN-ß Gene Transcriptional...The Mechanism of Combinatorial...References |
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Virus infection leads to transient activation of the IFN-ß gene. It has been hypothesized that the inducer of the IFN-ß gene is the double-stranded RNA produced during viral replication and that induction can be mimicked by the synthetic double-stranded RNA poly(I):poly(C) (reviewed in Reference 7). The kinetics of accumulation of IFN-ß mRNA parallel the transcription rate of the IFN-ß gene. Thus, the transient activation is at least partly due to transcriptional activation followed by postinduction transcriptional repression and rapid degradation of the IFN-ß mRNA. The level of IFN-ß mRNA peaks at around 8 hours and then decreases to low levels by 20 to 24 hours. Inhibition experiments have shown that protein synthesis is not required for activation of the gene but it is required for its postinduction repression. Thus, transcriptional activation likely involves the posttranslational modification of preexisting transcription factors, whereas postinduction repression requires the synthesis of transcriptional repression proteins (reviewed in Reference 9).
Detailed studies of the effects of promoter mutations on virus
induction of the IFN-ß gene led to the identification of a highly
compact and remarkably complex organization of regulatory sequences.
The DNA sequences required for maximal levels of virus induction are
localized to the first 104 bp immediately upstream from the start site
of transcription. This region contains both positive and negative
regulatory elements (Fig 2) and can function as a
virus-inducible enhancer when located upstream or downstream of a
heterologous promoter.9 10
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The PRDs of IFN-ß (PRDI through PRDIV) were defined by a combination of deletion and saturation mutagenesis and by showing that they can confer virus induction on a heterologous promoter when present in multiple copies. An important point from these studies is that none of the PRDs alone is sufficient for virus induction, but two or more copies of each of these elements are capable of conferring virus induction on a heterologous promoter. Moreover, in the intact IFN-ß promoter, these elements interact synergistically to achieve maximal levels of virus induction in most cell types.
Deletions or mutations in the negative regulatory domain I of the
IFN-ß gene promoter led to an increase in basal transcription level
in the absence of virus induction when the mutant genes are stably
introduced into mammalian cells in culture. Thus, this region, which
overlaps the PRDII (Fig 2
), has been implicated in the stable
repression of the IFN-ß gene before virus infection. In contrast,
postinduction repression appears to occur directly through the PRDs,
because deletions or mutations of negative regulatory domain I do not
affect the postinduction repression. Moreover, multimers of
either PRDI or PRDII are sufficient for both induction and
postinduction repression.9
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IFN-ß Gene Transcriptional Activators |
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TopAbstractIntroductionThe IFN SystemOrganization of the Human...IFN-ß Gene Transcriptional...The Mechanism of Combinatorial...References |
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A large number of experimental approaches have been undertaken to identify and characterize the transcription factors that interact with each of the PRDs in the IFN-ß enhancer/promoter. Since virus induction of the IFN-ß gene does not require new protein synthesis, it was assumed that the regulatory factors are likely to require postranslational modifications to bind and/or activate the IFN-ß enhancer/promoter. Moreover, these factors must be activated by other signals in addition to virus (for review see References 9 and 10).
The PRDII Activators
Virus induction of the IFN-ß gene requires NF-
B binding to
PRDII.11 12 13 14 Three distinct but complementary observations
indicate that NF-B plays an important role in virus induction.
First, mutations at PRDII that decrease binding of NF-B decrease the
levels of virus induction in vivo. Second, in uninfected cells, NF-B
is found in the cytoplasm bound to its inhibitor IB,
but shortly after virus infection, IB is destroyed and NF-B is
translocated into the nucleus. Finally, antisense RNA against the p65
subunit of NF-B strongly decrease the levels of virus induction in
vivo. The fact that NF-B binds and activates transcription
from PRDII explains the unusual property of the PRDII element to
respond to a remarkably divergent set of inducers such as tumor
necrosis factor-, phorbol 12-myristate 13-acetate, and
lipopolysaccharide, all of which induce the nuclear
translocation of NF-B.15 Although NF-B is required
for virus induction of the IFN-ß gene, it is not the only protein
that plays a critical role in virus induction from the PRDII element.
This notion grew out of experiments in which it was shown that
mutations at the middle AT-rich part of PRDII that did not affect
NF-B binding had a strong detrimental effect on virus induction in
vivo.14 15 16 Thus, virus induction of the IFN-ß gene from
the PRDII element requires NF-B and another protein that
specifically recognizes the AT-rich part of PRDII. This protein was
recently identified as HMG I(Y).14 HMG I(Y) belongs to a
class of low molecular weight basic proteins originally identified by
their association with chromatin. Unlike HMG1, which contains the DNA
binding motif known as HMG box, the DNA binding domain of HMG I(Y)
consists of three highly basic repeat sequences. HMG I(Y) contacts the
middle AT-rich part of PRDII from the minor groove, whereas NF-B
recognizes the GC-rich ends of the same element through contacts from
the major groove (Fig 3). Mutations that interfere with
the in vitro binding of either NF-B or HMG I(Y) decrease the levels
of virus induction in vivo. Moreover, antisense RNA against HMG I(Y)
also decreased the levels of virus induction in vivo. Thus, binding of
both NF-B and HMG I(Y) is required for virus induction of the
IFN-ß gene. However, in contrast with NF-B, which is a strong
activator of transcription, HMG I(Y) does not function as a
typical transcriptional activator. Rather, HMG I(Y) appears
to work as an auxiliary factor for NF-B function. In vitro
experiments demonstrated that HMG I(Y) increases the affinity of
NF-B for PRDII by a mechanism involving direct protein-protein
interactions between HMG I(Y) and NF-B and alterations in DNA
structure.10
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The PRDIV Activators
A combination of saturation mutagenesis experiments and in vitro
binding studies revealed the presence of an essential ATF-2 binding
site within the PRDIV element.17 However, multiple copies
of the ATF-2 binding site alone are not virus inducible although they
are cAMP responsive. These observations suggested that sequences
flanking the ATF-2 binding site within the PRDIV element are required
for virus induction but are dispensable for cAMP induction.
Footprinting studies revealed that HMG I(Y) specifically interacts with
the DNA sequences flanking the ATF-2 site (Fig 3) and
mutations that interfere with HMG I(Y) binding significantly decrease
the levels of virus induction in vivo.18 Thus, like PRDII,
the PRDIV element is a composite regulatory unit containing binding
sites for both HMG I(Y) and a transcription activator. In
the case of PRDIV, however, the transcription activator
required for virus induction is an ATF-2 homodimer and/or an
ATF-2/c-jun heterodimer because these proteins were detected
in virus-inducible complexes assembled on PRDIV. Significantly,
these complexes also contain HMG I(Y) since antibodies directed against
HMG I(Y) interfere with their formation.18
The PRDI-III Activators
Although the PRDI and PRDIII elements were initially thought to be
distinct, the high degree of their sequence similarity and the
observation that most proteins that bind PRDI also bind PRDIII suggest
that these elements represent a functional duplication of the
same regulatory unit. The only protein that has been directly
implicated in virus induction of the IFN-ß gene from the PRDI-III
element is IRF-1.19 20 IRF-1 binds specifically to both
PRDI and PRDIII (Fig 3); high-level expression of IRF-1 in culture
cells activates the endogenous IFN-ß
gene,21 and antisense RNA against IRF-1 significantly
decreases the levels of virus induction in diploid
cells.22 However, the IRF-1 protein is present at very
low levels in uninduced cells, and mice devoid of the IRF-1 gene
efficiently respond to virus induction.23 Taken together,
these and other observations suggested that there appear to be
IRF-1–dependent and IRF-1–independent pathways of IFN-ß gene
induction.
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The Mechanism of Combinatorial Regulation of the IFN-ß Gene |
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TopAbstractIntroductionThe IFN SystemOrganization of the Human...IFN-ß Gene Transcriptional...The Mechanism of Combinatorial...References |
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An important concept that emerged from the studies of IFN-ß gene regulation is the combinatorial mechanism of virus induction. Maximal levels of virus induction require at least all four distinct PRDs that are not inducible in isolation. However, artificial enhancers can be created by multimerization of these elements. Surprisingly, these artificial enhancers acquire additional biological activities that are not evident in the context of the intact IFN-ß promoter. For example, the multimerized PRDII element responds, in addition to virus, to other inducers, such as tumor necrosis factor-
, phorbol
12-myristate 13-acetate, and
lipopolysaccharide.15 Similarly, the PRDIV and
PRDI-III elements are inducible by cAMP and IFNs,
respectively.18 24 However, the intact IFN-ß gene
promoter is activated only by virus.10 24 Thus,
the virus-inducible enhancer of the IFN-ß gene consists of
overlapping regulatory elements recognized by a distinct set of
transcription factors that can be activated by virus but also
by other extracellular signals. However, the intact enhancer responds
exclusively to virus infection. Another interesting property of these
artificial enhancer elements is that none of them is as active as the
wild-type IFN-ß promoter. As a result of these properties, we are
confronted with two intriguing questions: How does such an arrangement
of relatively weak transcription elements result in the generation of a
potent virus-inducible enhancer, and how is the specificity of the
signaling response maintained since each of these elements also
responds to other extracellular signals? The simplest explanation of
this apparent paradox is that the activity of the enhancer is due to a
combination of cooperative interactions between different transcription
factors that are coinduced upon virus infection and between their
simultaneous interaction with components of the basal
transcriptional machinery assembled at the TATA box. Thus, virus
infection would result in the assembly of a highly organized
protein-DNA complex on the enhancer, involving extensive protein-DNA
and protein-protein interactions (Fig 4). This
complex array of interactions would result in the formation of this
complex only in response to virus infection that induces all of the
transcriptional activators required for its formation. An
important aspect of the model shown in Fig 4 is the role of HMG I(Y) as
an architectural component required for the formation and stability of
this complex. HMG I(Y) is required for the activity of both PRDII and
PRDIV but does not function as a transcriptional activator
on its own. However, HMG I(Y) significantly enhances the DNA binding
affinity of both NF-B and ATF-2 for their respective recognition
sequences by a mechanism that involves alterations in the structure of
DNA and by directly interacting with both NF-B and ATF-2.
Remarkably, NF-B directly contacts ATF-2 and IRF-1, and these
interactions are enhanced by HMG I(Y).10 18 Thus, direct
protein-protein interactions are involved in the transcriptional
synergism between the distinct elements of the IFN-ß promoter.
Moreover, HMG I(Y) mediates both protein-DNA and protein-protein
interactions in the assembly of an IFN enhancer complex. A number of
recent observations24 further support this model. First,
alterations in the relative phasing of the NF-B, IRF-1, and ATF-2
binding sites strongly decrease the virus-inducible levels in vivo.
Second, HMG I(Y) is required for the formation of a highly cooperative
transcription enhancer complex in vitro. Finally, an ATF-2 variant that
does not interact with NF-B and HMG I(Y) does not support
synergistic transcriptional activation in vivo.24 Thus,
the activation of the IFN-ß gene promoter by virus infection appears
to require the assembly of a stereospecific transcription enhancer
complex.24 25 The assembly and stability of this complex
require extensive protein-DNA and protein-protein interactions.
After the assembly of the enhancer complex, the activation domains of
the transcription factors must interact directly or indirectly with
components of the basal transcriptional apparatus and
thereby stimulate mRNA synthesis.
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Regulation of gene expression through the formation of stable enhancer complexes such as in the case of IFN-ß has some significant advantages. First, these complexes stimulate transcription synergistically. That is, the magnitude of transcription observed by the intact enhancer is well in excess of the sum of transcription elicited by each activator alone, even in multiple copies. These observations suggest that the enhancer complexes are either exceptionally stable and/or the activation domains of the transcription factors may form a novel surface that maximally interacts with the basal apparatus. Second, the specificity of gene activation in response to extracellular signals is achieved by the simultaneous induction of all of the components of the complex. Thus, the formation of transcription factor complexes consisting of specific members of different families of transcription factors provides a means of integrating multiple signaling pathways to target the activation of specific genes.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This review is dedicated to the memory of my friend and colleague Christos Cladaras, who died on August 10, 1994.
Received May 16, 1995; first decision August 23, 1995; accepted January 17, 1996.
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References |
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TopAbstractIntroductionThe IFN SystemOrganization of the Human...IFN-ß Gene Transcriptional...The Mechanism of Combinatorial...References |
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