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,From the Institut für Biologie III der Universität Freiburg, Schänzlestrasse 1, D-79104 Freiburg im Breisgau, Germany
INTRODUCTION
The Complete Chicken Lysozyme Locus Comprises the Regulatory Unit
of Transcription
The Role of Chromatin Architecture in Gene Regulation
The Role of Positive and Negative Cis-regulatory Elements in
Lysozyme Locus Activation
Incomplete Gene Loci Do Not Form Stable Transcription
Complexes
Perspectives
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
INTRODUCTION Gene loci of higher organisms have complex
structural features. In some cases their coding regions occupy many,
even hundreds, of kilobases of DNA. Additionally, the sequences that
contain the information for the correct spatial and temporal regulation of a particular gene locus during development often exceed the extensions of the coding region by severalfold. The question of what
type of information is encoded in these vast amounts of DNA has puzzled
researchers from the beginning.
It is now clear that eukaryotic genes are regulated by a number of
different cis-regulatory elements distributed over large distances. A
convenient way to assay the number and the distribution of
cis-regulatory elements has been the mapping of
DHS1 in chromatin. Such local
chromatin perturbations are in most cases caused by the binding of
transcription factors to their cognate DNA sequences. The pattern of
DHS can undergo dramatic developmental changes, indicating a change in
the activity of cis-regulatory elements. In addition, the analysis of
protein-DNA interactions at a single-nucleotide resolution level
in vivo has demonstrated that, depending on the
developmental stage, different combinations of transcription factors
can occupy the same cis-regulatory element (1, 2). These experiments
indicate that the transcriptional activation of a gene locus is
achieved by the cooperation of several different cis-regulatory
elements, which, in turn, assemble transcription factors in a
sequential, developmentally controlled fashion. However, the assembly
of active transcription factor complexes on natural genes does not
occur on naked DNA but in a chromatin context, where nucleosome-DNA
interactions have to be counteracted. Hence, the activation of a gene
locus requires at least the following steps: the perturbation of
chromatin structure by the binding of transcription factors on
cis-regulatory elements, the developmentally controlled reorganization
of transcription factor complexes, the assembly of the basal
transcription machinery and its interaction with upstream regulatory
elements, the onset of mRNA synthesis, and, in many cases, the
maintenance of an active transcriptional state during multiple rounds
of DNA synthesis.
How can the molecular basis of locus activation be experimentally
studied? While the basal activities of individual cis-regulatory elements of particular gene loci can be analyzed by transient and
stable transfection experiments, the molecular mechanism of activation
of a gene locus from the transcriptionally silent state can only be
studied in a developing system, preferentially in transgenic animals.
The ideal model locus should be small, thus facilitating the
manipulation of individual cis-regulatory elements within the context
of an entire genomic locus, and it should be extensively characterized
on the molecular level. In addition, to dissect the role of different
cis-regulatory elements in the developmental control of gene locus
activation, it should be possible to follow cell differentiation
experimentally, thus enabling the linkage of a stage-specific chromatin
structure with the transcriptional activity of the gene. Here, we
summarize recent studies on the molecular basis of the transcriptional
activation of the chicken lysozyme locus, which may serve as a paradigm
for other developmentally regulated eukaryotic gene loci.
The Complete Chicken Lysozyme Locus Comprises the Regulatory Unit
of Transcription The chicken lysozyme gene is expressed in the mature oviduct and
in cells of the myeloid lineage of the hematopoietic system (3, 4). In
myeloid cells the gene is up-regulated during the differentiation of
multipotent myeloid progenitor cells to mature granulocytes and
macrophages (5, 6). The structural dimensions of the chicken lysozyme
locus are defined by an increased general DNase I sensitivity of
chromatin over an array of 24 kb around the transcribed region (7). All
DHS and thus also all cis-regulatory elements are confined within this
chromatin domain (5, 6, 8, 9). Transfection analysis revealed three enhancers (at
Experiments in transgenic mice demonstrated that the complete,
structurally defined lysozyme gene locus is specifically expressed in
the right cell type (macrophages) and is unaffected by chromosomal position effects (15). The individual contributions of the different cis-regulatory elements to differentiation-dependent
transcriptional activation of the entire gene locus were revealed by
analyzing deletion mutants (16). Each construct with a deletion of one enhancer region supports macrophage-specific expression. However, position independence of expression is lost as soon as one essential cis-regulatory region is deleted. Thus, for correct locus activation in
development the cooperative action of all cis-regulatory elements is
necessary. At present, the role of the domain border fragments remains
elusive, since their deletion does not abolish copy-number dependence
of expression. Only if one enhancer region in addition is deleted is a
substantially higher incidence of ectopic expression observed as
compared with constructs with domain border fragments, together with
the abrogation of position independence. The notion that a complete
gene locus is resistant against genomic position effects has been used
to correctly express transgenes for which the structural and functional
extensions were not known, by introducing large yeast artificial
chromosomes into the germ line of mice (17, 18).
The Role of Chromatin Architecture in Gene Regulation The question now emerges as to whether a gene locus is completely
defined as a collection of cis-regulatory elements, which, in turn, are
defined by clusters of trans-factor binding sites separated by inert
DNA sequences or whether there is more to it than that. How do the
coordinated interactions between the cis-regulatory elements take place
and which role does chromatin structure play in this process? By
analyzing the chromatin structure of the lysozyme locus in chicken
macrophage cell lines, we determined the structural reorganization of
the various cis-regulatory elements at different developmental stages
(6). It turns out that the chromatin of the lysozyme locus is
reorganized in several steps, depending on the differentiation stage of
the cells (Fig. 1). The lysozyme gene in multipotent progenitor cell
lines is transcriptionally inactive and exhibits the chromatin
configuration characteristic for lysozyme non-expressing cells. Only
the DHS at the The results of our structural studies suggest that the correct
alignment of transcription factor-binding sites with respect to the
position of nucleosomes is essential for their undisturbed interaction.
Chromatin at the inactive state of the gene seems to be preset and
seems to fold the gene locus into a distinct three-dimensional
structure, thus leading to a precise spatial alignment of DNA
sequences. Based on these observations, we hypothesize that every DNA
sequence on a gene locus serves a purpose. Support for this idea comes
from experiments in which constructs containing combinations of very
short fragments encompassing only the minimal regulatory regions of the
lysozyme locus were analyzed in transgenic mice. These constructs were
not expressed.2 One of the
reasons for their failure might be that they are unable to support the
gradual chromatin rearrangements necessary to activate the gene locus
during cell differentiation. In this context it is also interesting to
note that deletion of a single DHS of the major upstream control region
of the human The Role of Positive and Negative Cis-regulatory Elements in
Lysozyme Locus Activation We showed that the chromatin structure displayed by the lysozyme
locus in the various chicken cell types is faithfully reformed in
lysozyme expressing and non-expressing cells of transgenic mice. This
holds true for the DHS and the nucleosomal phasing pattern as well as
for the reorganization of the Our structural analyses might present a clue to the role of the
What is the role of the promoter in lysozyme locus activation? To
answer this question we analyzed a construct carrying the complete
lysozyme locus with an internal deletion of the lysozyme promoter in
transgenic mice (Fig. 2). Transcription
from this construct was completely abolished (25). Surprisingly, the
deletion of promoter sequences uncovered a difference in the intrinsic ability of the individual cis-elements of the chicken lysozyme locus to
withstand repressing chromatin conformations. The formation of a DHS at
the
Taken together our data indicate that initial locus activation is
performed by the interaction of the Incomplete Gene Loci Do Not Form Stable Transcription
Complexes When complete gene loci are expressed independent of genomic
position, gene expression levels per gene copy are constant, whereas
incomplete gene loci express variable levels per gene copy, depending
on the site of integration. With deletion constructs expressing at a
low expression level per gene copy we could show that the formation of
DHS at the enhancers and the promoter is suppressed (26). The degree of
suppression of DHS formation is characteristic for each individual
mouse line (Fig. 2). In addition, we analyzed by MNase digestion the
chromatin of lysozyme transgenes expressed in an integration
site-dependent fashion (19). Individual mouse lines
carrying the same construct but with different expression levels were
compared. Thus, it could be determined whether all transgene copies
within a multicopy transgene cluster adopt the same chromatin
configuration or whether MNase patterns characteristic for active and
inactive loci are superimposed on each other. The conclusion is that
chromosomal position effects do not influence nucleosome positioning.
Instead, our analysis shows that integration site-dependent
expression of transgenes is associated with a mixed MNase pattern,
indicating the presence of active and inactive transgenes within the
same multicopy cluster. Hence, not all gene copies within a single multicopy transgene cluster are transcriptionally active (at a given
time). The proportion of active and inactive gene loci depends on the
chromosomal environment and the nature of the introduced mutation. The
idea of a dynamic equilibrium between the active and the inactive state
of a gene locus, which (in the case of transgenes) is a function of the
genomic integration site, is supported by a variety of studies. In a
series of elegant experiments, Fraser and co-workers (27) have
demonstrated that the human Perspectives Recent experiments studying the molecular basis of gene
locus activation in development have uncovered a stunning complexity of
regulatory principles. In particular, they point to an important role
of chromatin organization in this process. Pattern formation is based
on successive phenotypical changes of cells, whereby spatial
information, through cell-cell interactions, is often translated into a
change in cell identity. On the molecular level, these processes are
reflected at the different levels that control gene expression.
"Historic" information, that is information as to where cells have
been before and with whom they have communicated, is important for
correct pattern formation. In the same way, the order of chromatin
structure reorganization during the various cellular differentiation
states may be important for correct gene locus activation. If this
process is disturbed, something goes wrong. This concept will
undoubtedly influence the design of experiments examining the molecular
basis of gene expression control.
6.1 kb, 3.9 kb, and 2.7 kb), a hormone-responsive element (1.9 kb), a silencer element (2.4 kb), and a complex promoter (see Refs. 10 and 11 and Fig.
1). The borders of the DNase I-sensitive
domain coincide with sequences binding to the nuclear matrix in
vitro (12), suggesting that the lysozyme locus forms a chromosomal
loop (13). However, at present it is unclear whether these sequences
are firmly attached to the nuclear matrix in vivo (14).
Fig. 1.
A model for the developmental reorganization
of chicken lysozyme chromatin. Chromatin structure of the chicken
lysozyme locus 5
-regulatory region in different cell types is shown.
The positions of cis-regulatory elements as well as their nature are indicated. Hypersensitive DNase I cleavage sites are indicated as
non-histone proteins (various shapes) and by the indication DHS. Phased nucleosomes determined by MNase digestion
analysis and indicated by a regular 150-200-bp distance of MNase cuts
are depicted in dark gray; light gray nucleosomes
indicate areas with no prominent MNase cleavage sites. UPF,
upstream promoter factors binding to a stimulatory element around 200 bp upstream of the transcriptional start site; TFIID and
Pol II, basal transcription machinery; E,
enhancer; S, silencer; GM/CFC,
granulocyte/macrophage colony-forming units.
[View Larger Version of this Image (30K GIF file)]
2.4-kb silencer is present. At the myeloblast stage
DHS appear at the 6.1-kb enhancer, the 3.9-kb enhancer, and at the
promoter. At subsequent differentiation stages, the DHS at 2.4 kb
disappears and a DHS at the 2.7-kb enhancer is formed.
Transcriptional activity increases from a very low level in myeloblasts
to a 100-fold higher activity in bacterial
lipopolysaccharide-stimulated, activated macrophages. These experiments
correlate a high transcriptional level of the lysozyme gene with
conditions where all enhancers are active and where the silencer
element has been inactivated. Subsequent studies used MNase to probe
for specifically positioned (phased) nucleosomes in the complete
5-regulatory region of the lysozyme locus. In the transcriptionally
inactive state phased nucleosomes are located at most cis-regulatory
elements (19), as schematically depicted in Fig. 1. Each cis-regulatory
element shows a unique structural organization, with transcription
factor-binding sites specifically arranged with respect to nucleosomes.
Transcriptional activation results in significant rearrangements of
chromatin structure, which, however, are of different natures in
different cis-regulatory elements. At the promoter we see a regularly
spaced MNase pattern indicative of the presence of phased nucleosomes. After gene activation we see a perturbation of this pattern. The same
is found at the 6.1-kb enhancer. In contrast, as in the case of the
mouse albumin enhancer (20), nucleosomes seem to be actively positioned
after the activation of the 3.9-kb enhancer. The situation is even
more complicated at the 2.4-kb silencer/2.7-kb enhancer region.
Here, nucleosomes seem to be specifically positioned in the presence or
absence of a DHS at the silencer element, indicating that transcription
factor assembly occurs on their surface, similar to what is observed at
the mouse mammary tumor virus promoter (21).
-globin locus, the LCR, when analyzed in transgenic
mice in the context of the complete -globin locus, leads to a
breakdown of position independence of expression (22). This is in
contrast to what is observed with smaller constructs in which sequences
between the LCR and the -globin genes have been deleted. Here, it
may be speculated that, in analogy with the tethered loop model of gene
silencing put forward by Pirrotta (23), transcription factors binding to high affinity binding sites on core enhancer elements of natural gene loci have to recruit proteins on weaker binding sites on flanking
sequences. All elements may be necessary to bridge the large distances
to the promoter and to fold a gene locus into the active
conformation.
2.4-kb/2.7-kb region after terminal
macrophage differentiation (19), demonstrating that the same chromatin
rearrangements take place in both species. Our experiments with
deletion mutants of the lysozyme locus in transgenic mice demonstrated
that each enhancer region is capable of driving expression in mature
macrophages (16). We then asked how the different cis-regulatory
elements cooperate during earlier stages of cell differentiation. To
this end, we analyzed the time course of transcriptional activation of
wild type and mutant lysozyme locus constructs during in
vitro differentiation of myeloid precursor cells isolated from the
bone marrow of transgenic mice (24). In early macrophage precursor
cells the 6.1 kb and 3.9-kb enhancers, the promoter, and the
silencer element are DNase I-hypersensitive, whereas the 2.7-kb
enhancer is not (6, 10, 19). Our experiments demonstrate that a
construct carrying only the early (6.1 kb and 3.9 kb) enhancers is
capable of activating the lysozyme locus at the same developmental
stage and that transcription is up-regulated with the same kinetics as
the wild type locus carrying all cis-regulatory elements. We conclude
from these experiments that the early enhancers are responsible for
locus activation and that the onset of chromatin rearrangement at those
elements is coupled with the onset of mRNA synthesis. In turn,
since a deletion of the 2.4-kb silencer/2.7-kb enhancer region has
no influence on the locus activation kinetics, this implies, in
addition, that the silencer element does not repress the action of the
early (6.1 kb and 3.9 kb) enhancers. In concordance with the
chromatin data, a construct in which the 6.1-kb enhancer has been
deleted shows a delay in transcriptional activation.
2.4-kb element. We have demonstrated that the silencer element and
the immediately juxtaposed enhancer element are each organized in a
positioned nucleosome and most likely form an integrated cis-regulatory
element (Fig. 1). The spacing of binding sites is such that they may
face the same side on each nucleosome, thus bringing them into close
contact (19). The exact position of the nucleosomes is not yet known
and awaits the structural analysis of this region at the
single-nucleotide resolution level. However, chromatin rearrangements
at the 2.4-kb and 2.7-kb elements are strictly parallel, and the
appearance of MNase and DNase I-hypersensitive sites at the
enhancer correlates with the disappearance of such sites at the
negative regulatory element, indicating that factor binding at both
elements is mutually exclusive. Taken together, we regard it as most
likely that the 2.4-kb element is repressing the macrophage-specific
2.7-kb enhancer element at early developmental stages of myeloid
differentiation.
2.4-kb silencer element was unaffected, and also the DHS at the
2.7-kb enhancer element was formed, albeit with different intensity,
depending on the chromosomal position. In contrast, DHS formation at
the early 6.1-kb and 3.9-kb enhancers was abolished. Obviously, in
the initial activation of the lysozyme locus the early enhancers have
to interact with the promoter to form a stable enhancer-promoter
complex. Hence, the chicken lysozyme locus harbors no single element
with dominant chromatin opening function that is sufficient for locus
activation. Although elements (2.7-kb enhancer/2.4-kb silencer) exist
that are able to reconfigure the chromatin promoter independently, they
act later in cell differentiation, and their chromatin reorganizing
capacity is limited to their site.
Fig. 2.
Chromatin structure of the various chicken
lysozyme constructs in transgenic mice. A summary of chromatin
structure analyses of different constructs in different cell types of
transgenic mice is indicated on the left. At the
top of each panel the 5-region of the chicken
lysozyme constructs with specific deletions indicated as black
triangles is depicted. The main transcription start is indicated
by a horizontal arrow: black arrow, high level
transcription; striped arrow, variable transcriptional level
due to position effects. Exons 1 and 2 are symbolized by gray
boxes. Black vertical arrows, DHS displayed at wild
type strength irrespective of the chromosomal location of the
transgene; gray vertical arrows, 2.4- and 2.7-kb DHS
displaying changes in intensity according to the developmental stage of
the cells; striped vertical arrows, DHS forming with
variable efficiency depending on the chromosomal position of the
transgene. A, construct carrying the full set of
cis-regulatory elements; B, construct carrying a promoter
deletion; C, construct carrying a deletion of the late
enhancer region; D, construct carrying a deletion of the
early enhancer region. LPS, bacterial lipopolysaccharide;
E, enhancer; S, silencer; H, hormone-responsive element; P, promoter.
[View Larger Version of this Image (19K GIF file)]
6.1-kb and 3.9-kb enhancers
with the promoter. Maximal transcriptional activity is achieved by the
inactivation of the silencer element and the simultaneous activation of
the 2.7-kb enhancer (Fig. 1). One question, however, is immediately
apparent: if the early enhancers are sufficient to activate the
lysozyme locus at the correct developmental stage, why is the complete
locus necessary for position-independent expression?
-globin LCR-promoter interaction is
dynamic and switches between several promoters of the downstream
located globin genes (25). The authors also analyzed certain transgenic
mouse lines carrying deletion mutants of the complete -globin locus,
which render the transgene susceptible to genomic position effects. The
same level of steady state mRNA was observed in each cell; however, in contrast to the complete locus, not all cells show primary transcript synthesis at the same time (22), indicating that in each
cell the interaction of the LCR with the promoter is unstable. In a
different study it was shown that enhancers, when analyzed in stably
transfected cells, act as on-off switches, rather than by increasing
transcription rates. It was concluded from these experiments that
enhancers increase the probability of forming a stable transcription
complex at the promoter by antagonizing repressive chromatin structures
(28). Translated into a situation where several cis-regulatory elements
have to cooperate, this result indicates that the stability of the
interaction of transcription factor complexes on a given gene locus is
decisive for its sustained activity. In the case of the lysozyme locus
this would imply that one enhancer region is sufficient to activate the
lysozyme locus; however, to reproducibly maintain transcriptional
activity and an active chromatin structure at all chromosomal
locations, all cis-regulatory elements are necessary.
FOOTNOTES
To whom correspondence should be addressed: Molecular Medicine
Unit, University of Leeds, St. James University Hospital,
Clinical Sciences Bldg., Leeds LS9 7TF, United Kingdom.
ACKNOWLEDGEMENTS
We thank Dr. Nicole Faust and Dr. Christoph Redies for critically reading the manuscript and for helpful comments.
REFERENCES
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