2 Department of Pediatrics, Division of Gastroenterology and Nutrition, and 3 Department of Molecular, Cell, and Developmental Biology, School of Medicine, University of California, Los Angeles 90095; and 1 Department of Biology, California State University, Northridge, California 91330
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ABSTRACT |
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The polymeric Ig receptor (pIgR) is a critical component of the mucosal immune system and is expressed in largest amounts in the small intestine. In this study, we describe the initial characterization of the core promoter region of this gene. Expression of chimeric promoter-reporter constructs was supported in Caco-2 and HT-29 cells, and DNase I footprint analysis revealed a large protein complex within the core promoter region. Site-directed mutagenesis experiments determined that elements within this region serve to either augment or repress basal activity of the human pIgR promoter. Band shift assays of overlapping oligonucleotides within the core promoter identified eight distinct complexes; the abundance of most complexes was enhanced in post-confluent cells. In summary, we report the characterization of the human pIgR promoter and the essential role that eight different nuclear complexes have in controlling basal expression of this gene in Caco-2 cells.
upstream stimulatory factor; interferon response element; interferon response factor; adaptive immunity
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INTRODUCTION |
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THE HUMAN POLYMERIC IG RECEPTOR (pIgR) is a critical component of the mucosal humoral immune system as it transports Igs across the epithelial barrier (1). After synthesis, pIgR is targeted to the basolateral membrane where it binds noncovalently with high affinity to both the IgA dimer and pentameric IgM (19, 28). The Ig-receptor complex then translocates to the apical surface where it is cleaved by an unidentified protease. A portion of pIgR called secretory component remains attached to the Ig and has been shown to protect IgA and IgM from degradation by proteolytic enzymes (1).
The expression of pIgR mRNA is tissue and age specific and is also regulated by several cytokines, hormones, and growth factors (20). During the suckling phase of rodent development, intestinal pIgR expression is nearly undetectable; however, after weaning pIgR levels increase >20-fold (16). pIgR protein and mRNA are highly expressed in the epithelial cells of the small and large intestine and to a lesser extent in the liver, kidney, lung, salivary gland, mammary glands, and endometrium (20). In human and rodent intestine, pIgR expression is most abundant in the less well-differentiated epithelial cells that reside in the crypt compared with the more mature cells of the villus (2, 3, 31).
Nuclear run-on assays demonstrated that interferon- (IFN-
),
tumor necrosis factor-
(TNF-
), and interleukin-4 (IL-4) augment pIgR mRNA expression at the level of transcription, and the
mechanism by which these cytokines regulate pIgR
transcription has recently been elucidated (18, 24). An
interferon response element (ISRE) located on exon 1 of the human gene
was identified (25) as the site that confers
IFN-
-induced expression via the intermediate synthesis of interferon
response factor-1 (IRF-1). The human promoter also contains a nuclear
factor-
site that directs TNF-
-induced expression and a signal
transducer and activator of transcription (STAT) site located in intron
1 that controls IL-4-induced transactivation (27, 29). An
androgen response unit was also identified in the human promoter
(31), and an active glucocorticoid response element
was identified in the murine gene (13).
The basal expression of the immediate promoter region of the human
pIgR gene was recently examined (11). A
putative E-box located between nt 65 to
70 relative to the start of
transcription was found (11) to activate basal expression
in intestinal HT-29, gastric adenocarcinoma (AGS), and Calu-3 cells;
however, the identity of the transcription factor(s) that interacted
with the element was not elucidated. An inverted repeat sequence (IRS)
located immediately downstream of the E-box (
52 to
65) was
determined to bind to an unidentified nuclear factor; however, when the
IRS site was mutated, basal promoter activity was unaltered
(11). Transcriptional activity of nested deletion clones
also suggested that the region between
83 and
372 was
transcriptionally active; however, these potential sites were not
further evaluated in the study (11).
Using the murine pIgR promoter, we (16)
identified both a putative activator (78 to
70) and a repressor
(
62 to
52) element in the immediate promoter region in Caco-2 human
intestinal cells. Mobility shift assays indicated the presence of an
E-box at positions
75 and
70, and overexpression and supershift
assays suggested that the basic helix-loop-helix (bHLH) proteins
upstream stimulatory factor-1 and -2 (USF1 and USF2) upregulated basal
promoter activity (16). The murine promoter also contains
an IRS site, and clones containing mutations in the region that
overlapped with the IRS site (
62 to
52) identified evidence of
repressor activity. The nuclear protein(s) responsible for the
repressor activity was not identified by band shift assays.
To further characterize the mechanism by which the human pIgR gene is regulated, we focused on defining the elements that control its basal level of expression. Deletion and site-directed mutations of various elements within the core promoter were transiently transfected into human intestinal (Caco-2 and HT-29) cell lines to determine the elements that are required for full promoter activity. DNase I footprints and DNA binding assays were used in combination to further define the critical elements that control the basal expression of the gene.
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EXPERIMENTAL PROCEDURES |
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DNA cloning and substitution mutagenesis.
Four sense oligonucleotides [600/
579
(5'-gcaatctTACGACAGCCACTCCTGCCACC),
234/
212
(5'-gcaatctAAGCGACAGAAGAGCATCTT),
210/
181 (5'-gcaatctCGCTTGACATTCTGTCCCTCATCCTGAAGC), and
119/
108
(5'-gcaatctCCAGCCAGGAAGGCCAAAAT)] and an antisense
oligonucleotide [+55/+76 (5'-ataagcttCAGTTGGTAACCCCTGCCTC TC)] were
developed to PCR amplify various size products from human genomic DNA
(see Fig. 3) (11). The fragments were digested with
HindIII/BglII (restriction site indicated in
lowercase lettering) and subcloned into the pGL3-enhancer luciferase
reporter vector (Promega), as previously described (16).
Clones hpIgR
600/+76/E-Luc, hpIgR
234/+76/E-Luc, hpIgR
210/+76/E-Luc, and hpIgR
119/+76/E-Luc were sequenced to define their size
and authenticity.
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Identification of putative DNA cis-elements. The TRANSFAC database (GBF, Braunschweig, Germany) was used to identify the putative DNA cis-elements in the upstream region of the human pIgR gene (10).
Cell culture, transfection, and transfection procedure.
The human intestinal (Caco-2) and Chinese hamster ovary (CHO) cells
were maintained and transfected by the calcium phosphate method, as
previously described (16). HT-29 cells were obtained from
American Type Culture Collection and maintained in DMEM with 20% fetal
bovine serum, 200 U/ml penicillin, and 200 µl/ml streptomycin at
37°C in 5% CO2 and switched to L-15 media for 48 h
before transfection. Transient transfections were performed using 1 pmol/well of all the luciferase-expressing constructs, and 0.5 µg/well of the pCMV--galactosidase vector was transfected as a
control for transfection efficiency and cell number. For comparison of
clones containing specific mutations, transfection efficiency was
controlled for with the use of Renilla luciferase, a
component of the Promega dual luciferase system. Cotransfection of
various concentrations of several USF expression vectors was performed
as previously reported (16). All samples were
rinsed twice and processed 48 h after transfection. Both
luciferase and
-galactosidase were measured as previously described
(12). Transfection of HT-29 cells was performed using electroporation with the RF module (Bio-Rad). Each pulse had 10 µg of
luciferase construct and 1 µg of either pCMV-
-galactosidase or
Renilla vector for 4 × 106 cells. This
mixture was then pulsed at 0% modulation, 0.2 kV, and 50 Hz for 2 ms,
with 1-s intervals for 5 bursts. The volume of the DNA-cell mixture was
100 µl. This mixture was immediately transferred into L-15 media with
serum using a 1-ml syringe and disbursed over six-well plates. The
plated cells were allowed to incubate in the humidifier at 37°C and
5% CO2 for 24 h.
Electrophoretic mobility shift assays and preparation of nuclear
extract.
Nuclear extracts were obtained from Caco-2 cells either 2 or 10 days
after seeding by standard methods (7). Cells seeded for 2 days were subconfluent, whereas those seeded for 10 days were confluent
for ~7 days. Electrophoretic mobility shift assays (EMSA) were
performed as outlined previously (16), using
probes A-G (see Fig. 3). Briefly,
various double-stranded oligonucleotides (see Fig. 3) containing a GATC
5'-overhang were labeled with the use of Klenow fragment and
[-32P]dCTP (3,000 Ci/mol). Approximately 2-5 × 104 cpm of probe and 2.5-5 µg nuclear extracts
were used for each reaction. Standard competition studies were run
using excess unlabeled oligonucleotide duplexes. To identify the
precise outer limits of the cis-element, competition studies
were performed using a series of oligonucleotides that were the same
length as the wild-type oligonucleotides and included 5- to 3-bp
transversion mutations as specified within each figure (precise
oligonucleotides not shown). Antiserum against USF1, USF2,
CCAAT/enhancer-binding protein-
(C/EBP-
), C/EBP-
, C/EBP-
,
IRF-1, and cAMP-responsive element (CRE) binding protein (CREB) were
purchased from Santa Cruz Biotechnology and used to perform supershift studies.
DNase I footprinting.
To define the regions of DNA-protein interactions, we performed
DNase I footprint analysis according to methods established in our laboratory (16). The hpIgR
600/+22/E-Luc vector was cut with
HindIII, kinased with [
-32P]dATP (6,000 Ci/mol), and then cut with BglII. Samples were
electrophoresed on a 5% polyacrylamide gel, purified, and diluted to
6,000 cpm/µl. All footprints were performed with nuclear extracts
isolated from Caco-2 cells and dialyzed at a final concentration of 0.1 M KCl. Approximately 6,000 cpm of probe were mixed with 6 µg of
either nuclear extracts or BSA. Serial dilution of DNase I
was added to DNase reaction buffer (40 mM CaCl2,
10 mM HEPES, pH 7.9, 10% glycerol, 0.1 mM EDTA, 0.05 mM KCl, 28 mM
2-
-mercaptoethanol, and 0.1 mM BSA). Digestion with DNase
I occurred for 1 min at 25°C and was terminated with stop solution
(10 mM EDTA, 0.2% SDS, 40 mM sodium acetate, and 50 µg/ml yeast
tRNA). Samples were purified with phenol and chloroform, precipitated
with ethanol, and run on a 6% polyacrylamide gel for 100 min at 50 W. The locations of the protein-DNA binding sites were determined by
running a DNA ladder sequenced by the Maxam-Gilbert method.
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RESULTS |
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Transient transfection of human pIgR clones into HT-29, Caco-2, and
CHO cells identified gene's core promoter.
Four clones containing different length fragments of the 5' region of
the human pIgR gene (hpIgR
600/+76/E-Luc, hpIgR
234/+76/E-Luc, hpIgR
210/+76/ E-Luc, and hpIgR
119/+76/E-Luc) were transfected into various cell
lines (Fig. 1). Transfection of Caco-2
and HT-29 cells with either hpIgR
600/+76/E-Luc or hpIgR
234/+76/E-Luc resulted in promoter activity 10- to
20-fold higher than the promoterless pGL3-E vector. In contrast, in CHO
cells, promoter activity was only slightly higher than that observed
with the promoter-less vector.
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DNA footprint analysis of human pIgR's upstream core promoter
identified large footprint with multiple hypersensitivity sites.
DNase I footprint experiments of the immediate upstream
region of the promoter were performed using only nuclear extracts from
Caco-2 cells. The region was analyzed in the sense (5'3', Fig.
2A) and antisense directions
(3'
5', Fig. 2B). Footprint analysis in the sense
direction identified a rather large footprint containing three
hypersensitivity sites, suggesting the presence of DNA-protein
interactions located between
135 and
46 (Fig. 2A). When
this region was analyzed in the antisense direction, a slightly larger
footprint was identified that extends up to 190 nt upstream of the
start of transcription (Fig. 2B). Overall, these data
suggest that the immediate 5'-upstream region of the human
pIgR core promoter contains a large region that is capable of binding to Caco-2 nuclear extracts (Fig.
3).
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EMSA and transfection of reporter clones containing substitution
mutations in immediate promoter region defines several active elements.
To further define the critical elements in the core promoter region of
the hpIgR 210/+76/E-Luc vector, a series of 20 scanning mutagenesis clones was generated (some data not shown). Each
clone contained a different stretch of 10 mutated contiguous
nucleotides within the 286-bp minimal promoter (from
210 to +76)
(Fig. 3). Transfection of the majority of mutant clones in Caco-2 and
HT-29 cells had a level of activity that was similar to the nonmutated
wild-type clone (data not shown). The M2 region corresponded to the
TATA box (
26 to
30), and the promoter activity of the M2 clone was significantly lower than the wild-type vector, indicating the important
role of general transcription factors in controlling promoter activity
(data not shown).
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DISCUSSION |
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In this study, we analyzed the 5'-flanking region of the human
pIgR gene using transfection studies, DNase I
footprint analysis, and DNA binding assays. Transfection into both
intestinal (Caco-2/HT-29) and the nonexpressing CHO cell lines with the
human pIgR210/+76 promoter regions reveals the
specificity of the activity of the promoter (Fig. 1). DNase
I footprint analysis confirmed the presence of multiple footprints and
hypersensitivity sites located between nt
46 and
190 relative to
the start of transcription and within the minimal promoter of the gene
(Fig. 2). The pattern of footprints identified in the human promoter is
distinct from what we (16) have previously reported with
the murine gene. Regulation of pIgR expression does differ
between humans and rodents, because rodent and rabbit pIgR is expressed
in hepatocytes, whereas human pIgR is expressed in the
biliary epithelium (6). Moreover, expression in the
intestinal epithelium of humans occurs as early as 20 wk of gestation
and at 3 wk of postnatal life in rodents (20).
We employed an unbiased approach (scanning mutagenesis) to determine the regions of the core promoter that influence its activity. One drawback to such an approach is that the mutations can create an active region by introducing a cis-element. Such was the case with the M4 mutant, which increased promoter activity not by the removal of a repressor element, but instead by the introduction of an active E-box, which binds USF1 and USF2 and augments promoter activity (Fig. 4).
Probe B overlaps with both an E-box (71/
66) and the IRS
element (
65/
50), and competition studies shown in Fig. 5
demonstrate that the three complexes (B1
to B3) interact with the putative E-box. In
an analysis of the human pIgR promoter, Johansen et al.
(11) demonstrated the importance of the E-box in
conferring basal expression in AGS epithelial cells. Similarly, we
(16) demonstrated that the E-box located in a similar
region of the murine gene was also essential for driving basal promoter
activity in Caco-2 cells. The role of the leucine zipper proteins
(bHLH/LZ) USF1 and USF2 in augmenting basal expression of the murine
pIgR gene was confirmed by supershift and overexpression
assays using both wild-type and their corresponding DN vectors. Similar
studies were performed with the human core promoter and confirm the
role of USF1 and USF2 in transactivating the basal expression of the pIgR gene (Fig. 5D).
Transfection of a clone (M5) that disrupts the IRS site (65/
50)
failed to significantly alter transcriptional activity (Fig. 3 and data
not shown). A similar mutation in the murine promoter results in a
sixfold elevation of promoter activity compared with that of the
wild-type vector (16). Three base pair mutations covering
the entire IRS element (including an additional 7 nt downstream)
augmented basal expression in Caco-2 cells (Ref. 16 and
unpublished data). However, in the human promoter transfection of the
M5 clone only increased activity by 50% (data not shown). Despite
developing several overlapping oligonucleotides, we have not been able
to consistently detect a specific complex that binds to the IRS region
(data not shown). In contrast, Johansen et al. (11)
identified a complex that they attributed to binding at the IRS;
however, mutation of the site failed to alter transcriptional activity
in AGS cells and did not disrupt complex formation. Johansen et al.
(11) speculated that their failure to alter promoter activity might have occurred because they introduced transition mutations, which may have been insufficient to completely disrupt binding or alter transcriptional activity. In the current study, we altered the IRS by substituting with transversion mutations, yet
these mutations still failed to change transcriptional activity, raising the possibility that this site is only transcriptionally active
in the murine promoter (16).
The C complexes bind to a DNA element that is an insertion
in the human promoter and not present in the murine gene (Fig. 3).
Mutagenesis of this region suggests that the proteins that form the
C1 -C3 complexes have a role
in repressing basal promoter activity (Fig. 6). The EMSA competition
studies indicate that mutations of nt 107 to
99 (region
e-g) most substantially altered the
formation of the C3 complex, and these data are
most consistent with the transfection data demonstrating that the
promoter activity of the M10 clone was more significantly altered
compared with M9. Because mutations located in M9 should disrupt
binding of the C1 and C2
complexes, the transfection data indicate that these two complexes
may not alter promoter activity. Although the transfection data clearly
suggest that the alterations in the upstream portion (M10) of the
element most dramatically influence promoter activity, the three
C complexes are not as abundant in nuclear extracts of
subconfluent Caco-2 cells. Transient transfection studies performed in
this study occurred in subconfluent, dividing cells. Therefore, it is
possible that the magnitude of the C complexes' influence on pIgR promoter activity is more significant in
differentiated, nondividing cells than can be measured by standard
transfection assays.
Piskurich et al. (25) previously studied this region of the human pIgR promoter and determined that the complexes interacting in this area failed to be supershifted by antiserum to IRF-1, IRF-2, interferon-stimulated gene factor-3, and STAT1. However, the influence of this element on basal promoter expression was not evaluated, and the single complex detected previously does not resemble the complex detected in our analysis.
Through sequence homology, Piskurich et al. (25) also
identified another element that resembles an ISRE located between nt
128 and
138. This putative element spans the complexes identified with probes D and E. The previous analysis
(25) of this region may have not detected
D1-D2 or
E1-E2 because the studies did
not use a probe of sufficient length and the protein responsible for the D1 and D2 complex is
found in low concentrations in HT-29 nuclear extracts (data not
shown). Nevertheless, this element is clearly not binding
members of the C/EBP family of proteins, since antiserum toward
C/EBP-
, C/EBP-
, and C/EBP-
fails to supershift the complex
(21).
The faster migrating complex (D2) formed with
probe D interacts with the ATGGAG element located
from 125 to
120 and does not resemble any previously described
cis-element (Fig. 7A). An identical element
located from
173 to
168 was identified with probe G,
which itself was capable of competing for binding of the nuclear
extract with probe D (Fig. 7C, lane
20). In Fig. 7, competition with an oligonucleotide containing a
transversion mutation at location Df could only partially
compete for binding to the complex (Fig. 7, lane 11).
Similar results were obtained with probe G; however, when
transition mutations were substituted (GAG to AGA) the probe failed to
compete for the complex (data not shown). Whereas mutations (M11 and
M13) that selectively prevent the formation of the upper complex with
probe D only marginally increase basal expression, the M12
clone that results in a disruption of both complexes increases promoter
activity more than threefold (Fig. 7A). Therefore, the
significant upregulation of basal expression that occurs with the
clones containing mutations that disrupt both complexes suggests that
the protein(s) that binds to these elements functions in a cooperative
manner to repress promoter activity. Because the D complexes
are most abundant in postconfluent cells, their influence in
controlling pIgR expression may be more dramatic in
quiescent cells.
The most abundant complex that we identified in this study was the E complex, which also formed a very specific interaction with the identified cis-element (Fig. 8C). However, transfection studies failed to identify a role for this element in controlling pIgR expression (Fig. 8A). Nuclear extracts from subconfluent cells contained only a marginal amount of the complex and may have made it difficult to discern whether this complex has a positive or negative influence on pIgR promoter activity in the nondividing state. Of all the complexes identified in this study, only USF1 and USF2, which bind to the E box and augment promoter activity, are expressed in similar concentrations in pre- and postconfluent cells (Fig. 5C, lanes 12-15). Interestingly, pIgR expression in the intestine is most abundant in the less well-differentiated cells of the crypt and is decreased in the mature cells of the villus (2, 3, 31). Dai et al. (5) and Rottman and Gordon (26) have argued that subconfluent in vitro cells resemble cells in the intestinal crypt, whereas postconfluent cells are a more appropriate model for the differentiated and quiescent cells that populate the villus. Because complexes C and D appear to have an inhibitory effect on pIgR promoter activity, their role in the intestinal villus may be to diminish pIgR expression in vivo.
Site-directed mutagenesis of the element that forms the F complexes (TCCCAAGTAACA) results in a marginal 40% enhancement of basal promoter activity (Fig. 9B). Although this element appears to be unique, it resembles cis-elements recognized by two homeobox-containing proteins, Cdx-2 and Nkx-2.5 (9, 22). Whereas expression of Nkx-2.5 is limited to cardiac mesoderm and is essential for cardiac development, its counterpart, Nkx-2.3, is also expressed in gut mesenchyme during early development (22). Targeted disruption of the Nkx-2.3 gene results in early postnatal death and a marked reduction in the proliferation of epithelial cells of the intestinal villus (23). However, the element identified with probe F does not have a well-preserved Cdx-2 core element (ATTTACA), which is believed to be critical for its function (9). Nevertheless, Cdx-2 plays a critical role in controlling basal expression of several genes that are developmentally regulated in the small intestine, including sucrase-isomaltase, lactase-phlorizin hydrolase, and apolipoprotein B (9). While the murine pIgR gene is also developmentally regulated in a similar pattern to both sucrase-isomaltase and the apolipoprotein B genes, with the exception of the E-box, the murine promoter does not appear to contain any of the active elements identified in the human gene (11). The precise identification of the various protein complexes that bind to these distinct regions in the human promoter and their role in controlling basal and stimulated activity await further analysis.
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ACKNOWLEDGEMENTS |
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We thank Drs. M. Sawadogo and H. Towle for providing the USF1, USF2, USF1DN, and USF2DN expression clones.
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FOOTNOTES |
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This study was supported by National Institute of Child Health and Human Development Grant HD-34706 and Crohn's and Colitis Foundation of America Grant 016714.
Address for reprint requests and other correspondence: M. G. Martín, Dept. of Pediatrics, Division of Gastroenterology and Nutrition, School of Medicine, Univ. of California, 10833 Le Conte Ave., 12-383 MDCC, Los Angeles, CA 90095 (E-mail: mmartin{at}mednet.ucla.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
March 20, 2002;10.1152/ajpgi.00420.2001
Received 28 September 2001; accepted in final form 14 March 2002.
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