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Food Science and Human Nutrition Department, Center for Nutritional Sciences University of Florida, Gainesville, FL 32611-0370
3To whom correspondence and reprint requests should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONGene identification techniquesThe guanylin family of...Future directionsREFERENCES |
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KEY WORDS: • mRNA differential display • zinc • intestine • gene regulation • uroguanylin
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONGene identification techniquesThe guanylin family of...Future directionsREFERENCES |
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). The gastrointestinal
tract, being the primary absorptive and secretory site for zinc,
experiences both the acute effects of changes in dietary zinc intake
and the more chronic effects of zinc status. The gastrointestinal
system is subject to rapid cellular growth and differentiation to
perform a wide variety of functions and therefore is highly involved in
the modulation of gene expression. Its unique role in zinc metabolism
places it at a critical position to control zinc homeostasis through
subsequent alterations in gene expression (Cousins 1996
). Although much research has been directed at the
metabolism and homeostasis of zinc, there are major gaps in knowledge
of the zinc-responsive molecular and cellular mechanisms
responsible for maintaining health, particularly the genes involved.
The classic model for the direct interaction of zinc with gene
transcription comes from the promoters of the metallothionein genes in
the form of multiple short cis-acting DNA elements called
metal response elements
(MRE)4
(Culotta and Hamer 1989
). These MRE are necessary and
sufficient to confer the inducibility of metallothionein gene
transcription proportional to the levels of zinc present in the system.
Although early studies of these elements demonstrated that they were
binding sites for sequence-specific DNA binding proteins, classic
isolation and purification techniques for these proteins have met with
very limited success. Using a cloning method, an MRE binding
transcription factor (MTF-1) was identified by Radtke et al. (1993)
and shown to be essential for the zinc responsiveness.
It was recently demonstrated that, with six zinc finger motifs, MTF-1
likely uses three or four for MRE-specific DNA binding, whereas the
remaining one or two have properties consistent with a
metalloregulatory role due to a slightly lower affinity for zinc
(Chen et al. 1998
). It is of interest to note that
although transgenic mice with both the metallothionein-1 and -2 genes
knocked out are viable and appear quite normal, mice with the MTF-1
gene eliminated die in utero by d 14 of gestation, indicating an
essential developmental role for this transcription factor
(Günes et al. 1998
). How diverse the role of MTF-1
and related zinc-dependent transcription factors may be and how
dietary zinc may be involved in their regulation are questions that
remain to be examined.
In addition to direct mechanisms for zinc modulation of gene expression, indirect mechanisms sensitive to zinc status are likely to have a significant impact on gene regulation. These are pathways by which altered zinc status produces metabolic changes, such as modulations of enzyme activities or zinc-requiring signaling molecules. The change then may produce a feedback stimulus resulting in an alteration of gene expression. Although not directly affected by zinc and therefore much more difficult to study, these indirect mechanisms may still play a role in producing the effects associated with altered dietary zinc status, including zinc supplementation.
One of the major challenges facing biomedicine is to identify genes with altered expression under different physiological or pathological conditions. This endeavor is made all the more difficult by the fact that only a fraction of the genes in animal genomes have been identified or sequenced. To solve the latter problem, major public and private research initiatives are proceeding with efforts to sequence entire genomes and to catalogue the transcribed sequences contained within them through the production of expressed sequence tags (EST). To this end, GenBank and other, more specialized databases, such as dbEST, are growing at a tremendous rate and have become valuable resources.
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Gene identification techniques |
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TOPABSTRACTINTRODUCTIONGene identification techniquesThe guanylin family of...Future directionsREFERENCES |
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). However, in addition to being highly labor
intensive, library hybridization methods are fundamentally limited to
only two conditions, which is a significant constraint for nutritional
and developmental studies that require three or more experimental
conditions. The introduction of a reverse transcription–polymerase
chain reaction (RT-PCR) technique developed by Liang and Pardee (1992)
to identify previously unknown cancer genes has greatly
increased the efficiency of identifying unknown as well as known genes
regulated under specific conditions. This method, known as mRNA
differential display, is a powerful tool in meeting the challenge of
identifying previously unidentified regulated genes (Liang and Pardee 1995
, Wan et al. 1996
). Differential
display mutually benefits from and contributes to the various genome
projects by using GenBank to determine whether new EST sequence data
are from a known gene and by contributing EST with tissue specificity
and expression information to dbEST.
We used mRNA differential display to investigate the role of altered
gene expression during zinc deficiency, as well as zinc excess, in an
effort to identify the genes involved in zinc homeostasis and function.
Because the gastrointestinal system serves as both the primary
absorptive and the secretive site for zinc, it experiences some of the
most profound effects of altered zinc intake. As the primary site of
zinc absorption in the mammals, the small intestine has been the focus
of our initial efforts (Blanchard and Cousins 1996
). Our
studies consist of a classic approach with four dietary groups. Young
adult male Sprague-Dawley rats were housed for 15 d under one
of the following conditions: (1) zinc deficiency (-Zn),
(2) normal zinc (control), (3) pair-fed/normal
zinc (PF), and (4) zinc supplementation (+Zn). In addition
to records of body weight and food consumption maintained during the
study, controls for zinc status also included serum zinc levels and
kidney metallothionein mRNA levels as assessed by northern blot
analysis.
Differential display of mRNA analysis was performed on small intestinal
total RNA pooled for each condition with an equal contribution of RNA
from each animal within that dietary group. In the first step of
differential display, the RNA was reverse transcribed using an anchored
oligo(dT) primer [e.g., T12(GAC)C] to select
only a subset of the poly(A)+ mRNA for conversion into cDNA. The second
step of differential display used the same anchor primer plus a
10-nucleotide arbitrary primer to amplify fragments in a PCR that
incorporates a radiolabeled nucleotide. The arbitrary primer anneals to
only a fraction of the cDNAs and within this fraction at different
distances from the poly(A)+ tail, resulting in multiple PCR products or
EST (also called 3' EST if they are from the 3' end of the mRNA) that
represent only a small fraction of the original number of mRNAs. The
progressive subfractionation of the mRNA population results in a
reasonable number of EST that can be evaluated at one time but
consequently means that multiple combinations of primers and reactions
must be performed to effectively complete a survey of an mRNA
population of 20,000 (Bauer et al. 1993
).
After PCR, each set of radiolabeled EST was separated on a DNA sequencing electrophoresis gel, and the bands were detected by autoradiography so the radioactive intensity of each band could be compared between dietary conditions. Only EST bands with -Zn or +Zn intensities different from the control and PF band intensities were selected for cloning and confirmation. Cloning of the EST from the differential display gel was accomplished by separate PCR reamplification of each excised band to produce sufficient DNA for ligation into a plasmid. After ligation, transformation and plasmid preparation, restriction analysis and Southern blotting identified any heterogeneity among the EST clones. Individual clonal colonies were then used as probes to determine which one produced the differential signal.
Confirmation of the differential regulation indicated by the differential display gel with an independent method is essential because of potential artifacts associated with the differential display RT-PCR. Northern blots were prepared with pooled RNA from each condition and, after hybridization to radiolabeled EST probes, were visualized by autoradiography. Clones that confirmed the differential display regulation on northern blotting were then selected for sequence analysis. Improvements in the primer design and long-read high resolution gel systems, such as those available in the Genomyx LR Differential Display system (Beckman, Fullerton, CA), have decreased the incidence of false-positive results. Nevertheless, independent confirmation remains an essential component of every differential display project.
For clones containing confirmed regulated EST, DNA sequencing provided the information necessary to search GenBank to determine whether the differential display EST were produced from known genes. This identification was determined either by the identity of the EST sequence to a rat cDNA or by high homology to a cDNA found in other organisms, usually human or mouse. When the differential display EST had no good matches in GenBank, the sequence was compared with other EST in the National Center for Biotechnology Information/National Institutes of Health EST database, dbEST. Matches that were found in dbEST could often extend the sequence information for that cDNA, identify genes with homology to the EST and provide preliminary information on tissue distribution. Some EST had no good matches, indicating novel or previously unreported mRNAs; however, the incidence of this is rapidly decreasing as the EST databases grow larger.
We have identified a growing number of 3' EST for intestinal mRNAs with
altered expression due to zinc deficiency and include both genes that
would be considered general "housekeeping" genes and highly
specialized genes such as those for peptide hormones (Table 1
). Of these, only two of the EST match genes previously linked to
regulation by dietary zinc status. One of these EST was from the mRNA
for rat intestinal alkaline phosphatase II, and it was increased in
zinc deficiency and reduced in zinc supplementation. The regulation of
mRNA for this zinc metalloenzyme was not unexpected. Decreased alkaline
phosphatase activity in both the intestine and serum during zinc
deficiency is well established (Hambidge et al. 1986
).
It is interesting to note that although the enzyme activity decreases
in zinc deficiency, the mRNA levels are increased, which suggests that
decreased phosphatase activity causes increased production of mRNA via
a compensatory feedback loop.
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through the use of subtractive
cDNA library screening of rat small intestinal mucosa. The subtractive
library screening, however, only compared mRNA populations from two
dietary conditions, -Zn and pair-fed normal zinc, whereas
differential display compared these along with ad libitum–fed control
and +Zn rats at the same time. Analysis by differential display yielded
the surprising result that I-FABP not only was decreased in zinc
deficiency, as had been previously shown, but also was decreased in +Zn
rats and increased in the pair-fed group relative to controls. The
identification of I-FABP helped validate the ability of
differential display to effectively compete with subtractive cDNA
library hybridization procedures to identify nutritionally regulated
mRNAs.
Four genes, nominally described as housekeeping genes, were identified
by differential display as having intestinal mRNA levels modulated by
dietary zinc; these include the rat cis-Golgi p28, rat
proteasomal ATPase and the rat homologues of bovine ubiquinone
oxidoreductase subunits ASHI and CI-B9, all of which except the ASHI
subunit were increased in zinc deficiency. The functional significance
of these changes remains to be determined; however, they could be
linked to intracellular protein processing or degradation through
polyubiquitination pathways (Bonifacino and Weissman 1998
).
One EST that may indicate a link in the path leading to compromised immune status during zinc deficiency encodes for the rat homologue of the mouse immunoglobulin active J chain. This protein is required for the polymeric structure and secretion of IgMs and IgAs. The mRNA for this peptide is increased in -Zn but not altered in pair-fed or +Zn groups. The expression of this immune-related protein in the intestine occurs in the plasma cells below the epithelial layer. These cells are responsible for the production and secretion of gastrointestinal IgAs, a major component of intestinal immunity.
Of the two EST that identified peptide hormone precursor RNAs that were
elevated in zinc deficiency, the first was rat cholecystokinin (CCK).
This pluripotent hormone serves both endocrine and neurocrine roles,
including the regulation of pancreatic secretion and gastric emptying,
in addition to being a satiety factor (Niederau et al. 1994
). The fact that CCK mRNA levels are increased in zinc
deficiency led to the hypothesis that increased levels of CCK are
responsible for zinc-deficient anorexia. However, neither
subdiaphragmatic vagotomy before a zinc-deficient diet study nor
the administration of the CCKA receptor
antagonist Devazapide (MK329; Merck Research Laboratories,
Rahway, NJ) during the study was able to increase the food intake of
the -Zn group (unpublished data). CCK may instead function to
stimulate the pancreas and enzyme secretions, which are also severely
affected by dietary zinc deficiency.
The second hormone precursor EST, identified as preprouroguanylin, has
been of particular interest in the context of zinc function. The
differential display band indicated increased levels of this mRNA in
zinc deficiency, and subsequent northern blot analysis confirmed this
as a 2.5-fold increase in zinc-deficient levels compared with
normal levels (Fig. 1
). Although there was a 0.3-fold increase in pair-fed rats, there
was no increase due to zinc supplementation. On initial analysis of the
sequence data, the rat EST matched only one sequence in GenBank, the 3'
half of a recently reported cDNA for human guanylate cyclase activating
protein-II/uroguanylin precursor peptide (Hill et al. 1995
). The 5' portion of the rat cDNA then was cloned via 5'
rapid amplification of cDNA ends for further characterization of the
rat preprouroguanylin cDNA sequence (Blanchard and Cousins 1997
). Subsequent tissue distribution studies demonstrated that
although preprouroguanylin mRNA was also expressed in the colon,
stomach, kidney, thymus and testis, it was most highly expressed in the
small intestine. Additional analysis of kidney and thymus RNA revealed
that preprouroguanylin mRNA levels were not altered during zinc
deficiency, demonstrating the specificity of this gene regulation to
the gastrointestinal tract.
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The guanylin family of hormones |
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TOPABSTRACTINTRODUCTIONGene identification techniquesThe guanylin family of...Future directionsREFERENCES |
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). The prohormone is activated
extracellularly by proteolytic cleavage to produce a biologically
active 15- to 24-amino-acid, cysteine-rich peptide. Because of the
high cysteine content, four or more residues, the metal binding
potential of the peptides was evaluated but with negative results.
Instead, the cysteines form two sets of disulfide bridges that are
essential for the active conformation of the peptide. The functional
definition of the members of this family came from their ability to
bind to and activate the Escherichia coli heat-stable
enterotoxin (STa) receptor also known as intestinal guanylate
cyclase-C (GC-C), as well as from high sequence homology between
the active hormone peptides and STa. The activation of GC-C
initiates a cGMP cascade that results in stimulation of the cystic
fibrosis transmembrane conductance regulator (CFTR), which increases
the transport of chloride into the intestinal lumen (Chao et al. 1994
). Overall, this results in a net flux of water into the
gastrointestinal tract.
The GC-C activation by STa has been extensively studied as the
causative agent for traveler’s diarrhea, a secretory diarrhea produced
by excessive chloride and water transport into the intestinal tract.
Characterization of the toxin led to the identification of the
intestinal cell surface binding site that was determined to be a
membrane-bound guanylate cyclase, designated GC-C
(Schultz et al. 1990
). The endogenous ligand for this
receptor, however, remained elusive until the identification of the
peptide hormone guanylin from the intestine (Currie et al. 1992
). Of the currently identified guanylin family members,
uroguanylin is the most potent activator of GC-C, but it is still
only about one tenth as potent as STa, which is a superagonist to the
receptor. In the gastrointestinal tract, uroguanylin and guanylin are
secreted into the lumen and appear to have complementary expression and
pH optima for GC-C activation. Uroguanylin is more highly expressed
in the small intestine and is 100-fold more potent than guanylin in an
acidic environment of pH 5.0. Guanylin, on the other hand, is more
highly expressed in the colon and is fourfold more potent than
uroguanylin at pH 8.0 (Fan et al. 1997
, Hamra et al. 1997
). In this way, the two hormones appear to work
cooperatively to help maintain water balance in the gastrointestinal
tract. Uroguanylin, however, is also secreted into the bloodstream, and
it received its name by virtue of the fact that it was originally
purified from opossum urine. The presence of uroguanylin in the blood
with excretion through the kidney and the presence of GC-C
receptors in the kidney indicate that uroguanylin likely serves a role
in the coordination of overall water balance between the intestine and
kidney (Forte et al. 1996
).
The fact that uroguanylin mRNA is increased in zinc deficiency begins
to suggest a mechanistic explanation for the clinically documented
diarrhea resulting from zinc malnutrition. Because zinc deficiency has
the potential to alter hormonal systems, it appears that in the case of
uroguanylin there could be an increase in chloride and water secretion
into the intestine, possibly resulting in a secretory diarrhea. This is
an oversimplified view because the metabolism involved in water balance
is very complex and the CFTR activity is modulated not only by cGMP
pathways but also by cAMP and nitric oxide (NO). NO in particular has
been implicated as a causative agent in diarrhea, yet it has been shown
to both increase and decrease CFTR activity depending on the context of
the stimulus (Cui et al. 1997
, Izzo et al. 1998
). Interestingly, NO may also be involved directly with
zinc homeostasis, because one report indicates it is capable of
stimulating an intracellular redistribution of zinc (Berendji et al., 1997
).
Further investigation will determine whether the increased mRNA is caused by a direct effect of zinc on the preprouroguanylin gene or as a secondary event responding to something else that was altered by zinc status. This avenue of investigation, however, has been hindered by the lack of an intestinal cell line that expresses the uroguanylin gene. In addition, the mRNA observation does not necessarily translate into an increase in the mature hormone because the proteolytic activation (which likely results from a zinc endopeptidase) appears to be well regulated. More experiments at the level of the prohormone and mature hormone must be performed to answer this question.
There are two points that can be made in the context of an overview of
the zinc-regulated mRNAs identified thus far. First, the findings
that the two peptide hormones identified require extracellular
proteolytic activation and that both have increased mRNA levels suggest
that there might be a broader-based impact of zinc deficiency on
the activity of extracellular zinc peptidases involved in cellular
communication pathways. A relatively large number of extracellular
matrix metalloproteases (MMP), including collagenases and elastases as
well as endogenous inhibitors for these enzymes (tissue inhibitor of
metalloproteinase), have been identified and constitute a
growing field of study, especially regarding their role in immunology,
development, cancer and wound healing (Geisler et al. 1997
, Gomez et al. 1997
). These enzymes require
zinc for catalytic activity and probably obtain it from intracellular
sources during translation. Secretion of the holoenzyme could be
decreased during zinc deficiency. After secretion, however, the
affinity of the enzyme for zinc may be such that there is an exchange
of zinc with its environment, resulting in decreased enzymatic
activity. If serum zinc levels can be extrapolated to be a measure of
extracellular zinc levels, then there are certainly significant fluxes
in the levels of zinc, especially during deficiency, which may have a
direct effect on the activity of some of these enzymes and,
subsequently, their metabolic feedback pathways. Such a model is
presented in Figure 2
. Feedback pathways may include increased protein degradation of the
apoenzyme or decreased stimulus to a signal transduction pathway that
results in a compensatory response.
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Future directions |
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TOPABSTRACTINTRODUCTIONGene identification techniquesThe guanylin family of...Future directionsREFERENCES |
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FOOTNOTES |
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2 Supported by National Institutes of Health Grant
DK31127 (to R.J.C.), Institutional National Research Service Award
DK07667 and Boston Family Endowment Funds of the University of Florida.
Experiments with animals from the authors’ laboratory described in
this review followed the guidelines of University of Florida
Institutional Animal Care and Use Committee.
4 Abbreviations used: CCK, cholecystokinin; CFTR, cystic fibrosis transmembrane conductance regulator; EST, expressed
sequence tag; GC-C, guanylate cyclase-C; I-FABP, intestinal fatty acid binding protein; MMP, matrix metalloprotease; MRE, metal
response element; MTF-1, metal response element binding transcription factor-1; NO, nitric oxide; PCR, polymerase chain reaction; PF,
pair-fed/normal zinc; RT, reverse transcription; STa, E. coli heat-stable enterotoxin; -Zn, zinc-deficient; +Zn, zinc-supplemented.
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TOPABSTRACTINTRODUCTIONGene identification techniquesThe guanylin family of...Future directionsREFERENCES |
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