Tissue-specific and developmental expression of eukaryotic genes is regulated by multiprotein complexes assembled on enhancer and promoter sequences (reviewed in (1) ). Modular organization of target sites for transcriptional factors within the enhancers is believed to be a device for integrating signals transduced by the factors during the course of establishment and maintenance of the tissue-specific phenotype(2) .

Apolipoprotein AI (apoAI) ()is the major protein constituent of high density lipoproteins, which transport cholesterol from extrahepatic tissues to the liver for excretion (reviewed in (3) ). Liver-specific expression of the gene encoding apoAI is the outcome of multiple protein-DNA and protein-protein interactions involving ubiquitous and liver-enriched transcription factors(4, 5, 6, 7, 8, 9, 10) . The architectural requirements for these interactions are fulfilled by a tissue-specific enhancer located in the -222 to -110 region of the apoAI gene promoter(4, 5) . Within the enhancer, three sites (sites A, -214 to -192; B, -169 to -146; and C, -134 to -119) (5) are predominantly occupied by transcription factors present in liver nuclear extracts. Sites A and C are cognate sites for members of the nuclear hormone receptor superfamily (11) including RXR (6, 8) and HNF-4(9, 10, 12) , which activate apoAI gene transcription, and ARP-1(7, 9) , Erb EAR-2(), and Erb EAR-3/chicken ovalbumin upstream promoter transcription factor(9) , which repress it. Site B is an efficient response element for the liver-enriched factor HNF-3 (10) .

Since the apoAI regulatory apparatus responds to diverse stimuli (14, 15, 16, 17, 18, 19, 20) , we predicted that the precise composition of the multiprotein enhancer complex would be continually changing (9, 10) and suggested that repression mediated by ARP-1 may facilitate switching between alternative transcriptionally active states induced by different stimuli(8, 9) . Accordingly, the early growth response factor, Egr-1, was identified as a transcription factor that could overcome ARP-1-mediated repression of the apoAI gene and restore elevated activity of the enhancer(9) .

This paper demonstrates that Egr-1 activates apoAI gene transcription through two sites in the enhancer, which bind Egr-1 and display significant homology to the consensus Egr-1 binding site. It is further shown that Egr-1 contributes to the transcriptional activation of the apoAI enhancer in the absence of functional sites A, B, or C. These findings raise the possibility that control of apoAI gene transcription by Egr-1 may be a mechanism for overriding pre-existing regulatory constraints.

MATERIALS AND METHODS

Synthetic Oligonucleotides

Plasmids

Transient Transfection Assays

EMSA

RESULTS

Identification of Two Egr-1-responsive Elements within the apoAI Enhancer

Figure 1: Deletion mapping analysis of the apoAI promoter responsiveness to Egr-1. CAT reporter constructs (8 µg) under the control of the apoAI promoter (-256.AI.CAT) or the indicated deletion derivatives were cotransfected into HepG2 cells with pRSV--galactosidase plasmid (2 µg) in the absence or presence of the Egr-1 expression plasmid (pCMV5-Egr-1, 0.5 µg). For each construct, -fold activation by Egr-1 was expressed as the ratio of the CAT activity (normalized to -galactosidase activity) in the presence of pCMV5-Egr-1 to that in its absence. Filledbars, relative CAT activity of construct in the absence of Egr-1 expression plasmid; cross-hatched bars, relative CAT activity of construct in the presence of Egr-1 expression plasmid.

Collectively, these data indicate that the -256 to -133 apoAI promoter/enhancer region contains all the necessary elements for maximal responsiveness of the apoAI gene to Egr-1. In addition, the data suggest that this region is composed of more than one subregion, each contributing to the full responsiveness to Egr-1. Specifically, the -203 to -140 subregion responded to Egr-1, but the -187 to -140 did not. This suggests that sequences in the -203 to -187 region may be a part of an Egr-1-responsive element. This is consistent with the observation that deletion of the -256 to -192 region in the reporter -192AI.CAT reduces Egr-1 responsiveness. However, it does not explain why the responsiveness of the -203 to -140 region is less than half that of the -256 to -133 region. These findings argue for the presence of additional Egr-1-responsive elements either at -256 to -203, -140 to -133, or both. Comparison of sequences in and around -256 to -203, -203 to -187, and -140 to -133 with the established consensus sequence for Egr-1 binding CGCCCCCGC (24) revealed two sites, site E2 CGCCCCCAC (at positions -221 to -213) and site El AGCCCCCGC (at positions -189 to -181) each deviating by a single nucleotide (underlined) from the Egr-1 consensus sequence(24) . The region around -140 to -133 did not contain sequences with recognizable homology to the Egr-1 consensus (see Fig. 2A).

Figure 2: EMSA analysis of proteins binding to sites E1 and E2. A, the nucleotide sequence of the apoAI promoter region is shown. Numbers indicate location of nucleotides upstream from the transcriptional start site. The location of the enhancer elements A, B, C, E1, and E2 and the overlapping Sp1 site (see text) within this sequence are indicated. Regions spanned by double-stranded oligonucleotides used in EMSA including mutant oligonucleotides E1m and E2m containing C to A substitutions in the putative Egr-1 binding sequence are also shown. These mutations (at positions -186 and -218) are also indicated on the sequence. B and C, in vitro translated Egr-1 (lanes2-12) was tested for binding to site E1 (panelB) and site E2 (panelC) probes by EMSA. The following competitor oligonucleotides were included: lanes3-6, indicated molar excess of unlabeled oligonucleotide E1 (panelB) and E2 (panelC); lane7, Egr (Egr-1 consensus); lane8, Egrmut (Egr-1 consensus binding site mutant); lane9, apoAI site A (A); lane10, E1m (mutant site E1, panelB) or E2m (mutant site E2, panelC). Antibody specific for C/EBP (lane11) or Egr-1 (lane12) was included as indicated. D, EMSA binding reactions contain HepG2 cell nuclear extract and end-labeled site E1 (lane1) and site E2 (lanes2-13) probes. 200-fold molar excess of the following unlabeled competitor oligonucleotides was included as indicated: lane3, E2; lane4, E2m; lane5, apoAI site A (A); lane6, E1; lane7, Egr-1; lane8, Sp1; lane9, AP-2; lane10, AP-1; lane11, Oct-1. Antibody specific for Sp1 (lane12) or Egr-1 (lane13) was included as indicated.

Site E2 Binds Both Sp1 and Egr-1 but Site E1 Binds Only Egr-1

To determine whether E1 and E2 are bound by Egr-1 or other related factors in HepG2 cells, nuclear extracts prepared from these cells were subjected to EMSA analysis with the E1 and E2 oligonucleotide probes. The results in Fig. 2D, representative of binding reactions performed under various conditions using different preparations of HepG2 nuclear extracts, showed little, if any, nuclear factor binding to the E1 probe (lane1). In contrast, incubation of the nuclear extracts with the E2 probe resulted in multiple retardation complexes (lane2).

To identify the factor(s) in HepG2 cells that bind(s) preferentially to E2 despite the similar affinities of sites E1 and E2 for Egr-1 (data not shown), we undertook a systematic competition EMSA analysis using as competitors various double-stranded oligonucleotides containing binding sites for previously characterized transcription factors. As can be seen in Fig. 2D, the retardation complex formed with probe E2 was inhibited by excess unlabeled E2 oligonucleotide (lane3) but not by excess E2m oligonucleotide (lane4). Retardation complex formation was not inhibited by excess apoAI site A (lane5) or site E1 (lane6) oligonucleotides nor by excess Egr-1 consensus oligonucleotide (lane7). Together with the observation that the factors capable of binding to site E1 are absent in HepG2 nuclear extracts, these data provided strong support for the notion that the factor(s) that bind(s) to site E2 are different than Egr-1. This was further confirmed by supershift analysis of probe E2 retardation complexes using Egr-1-specific antiserum (lane13). The possible identity of this factor with the transcription factor Sp1 was indicated by the substantial inhibition of retardation complex formation by excess amounts of an oligonucleotide containing the Sp1 binding consensus sequence (lane8). Excess amounts of oligonucleotides corresponding to the binding sites for the transcription factors AP-2, AP-1, and Oct-1, on the other hand, did not interfere with retardation complex formation (lanes9-11). Supershift analysis using Sp1-specific antiserum (lane12) confirmed the presence of Sp1 in probe E2 retardation complexes. Indeed, upon re-inspection of the site E2 sequence, it was apparent that it contains two extensively overlapping transcription factor binding motifs, one for Egr-1 and another for Sp1 (see Fig. 2A). Note also that the C to A substitution in the mutated version of E2, i.e. E2m, affects both Egr-1 and Sp1 binding motifs, explaining the inability of the mutated site to bind either Egr-1 or Sp1.

Functional Analysis of Sites E1 and E2

Figure 3: Egr-1 responsiveness of sites E1 and E2. A, CAT reporter constructs containing sites E1, E2, and their mutant derivatives E1m and E2m (Fig. 2A) upstream of the apoAI core promoter (-41AI.CAT) were analyzed for Egr-1 responsiveness by transfection in HepG2 cells as described in the legend to Fig. 1. Relative CAT activity in HepG2 cells transfected with each reporter in the absence (filledbars) or presence of Egr-1 expression plasmid (cross-hatched bars) was determined as in Fig. 1. B, CAT reporter constructs containing nucleotide substitutions within the putative E1 and E2 enhancer elements of the apoAI promoter are shown on the left. Egr-1 responsiveness was determined as in A.

To evaluate the functional significance of sites E1 and E2 in the context of the activation of the apoAI enhancer by Egr-1, the E1 and E2 sites in -256AI.CAT were replaced by the mutant sites E1m and E2m, respectively, either each one alone or both in combination (see ``Materials and Methods''). The resulting reporters -256(E1m)AI.CAT, -256(E2m)AI.CAT, and -256(E1m.E2m)AI.CAT were then tested for their ability to respond to Egr-1 in transient cotransfection assays in HepG2 cells. As shown in Fig. 3B, the basal activity of each of these reporters did not differ significantly from that of -256AI.CAT, suggesting that sites E1 and E2 are not involved in maintenance of the basal activity of the apoAI enhancer in HepG2 cells. In contrast, the Egr-1-induced activation of -256AI.CAT (5.8-fold) was significantly compromised in -256(E1m)AI.CAT (1.9-fold) and -256(E2m)AI.CAT (4-fold), while -256(E1m.E2m)AI.CAT was totally unresponsive to Egr-1. These data indicate that both E1 and E2 sites are required for maximal responsiveness of the apoAI gene enhancer to Egr-1.

Both E1 and E2 Are Required for Egr-1 to Fully Overcome ARP-1-mediated Repression of the apoAI Enhancer

Figure 4: Requirement of sites E1 and E2 in Egr-1-mediated reversal of ARP-1 repression. CAT reporter constructs containing inactivating nucleotide substitutions within the E1 and E2 enhancer elements of the apoAI promoter were transfected into HepG2 cells alone (filledbars), in the presence of ARP-1 expression vector (1 µg, cross-hatched bars), and with the ARP-1 and Egr-1 expression vectors together (stippledbars). CAT activity of cell lysates was determined as in Fig. 1.

Egr-1 Responsiveness of the apoAI Enhancer Is Independent of Sites A, B, and C

Figure 5: Egr-1 activation of the apoAI enhancer in the absence of functional sites A, B, or C. CAT reporter constructs under the control of the apoAI core promoter (-41 to +397) with promoter sequences from the -222 to -110 containing nucleotide substitutions that eliminate protein binding to the sites (indicated as X). Egr-1 responsiveness was determined as in Fig. 1. Filledbars, relative CAT activity of construct in the absence of Egr-1 expression plasmid; cross-hatched bars, relative CAT activity of construct in the presence of Egr-1 expression plasmid.

DISCUSSION

The growing list of transcription factors that function through the 110-nucleotide span of the apoAI enhancer includes nuclear hormone receptors(6, 7, 8, 9, 10) , the hepatocyte-enriched factors HNF-3 (10) and C/EBP(9, 25) , and, as shown in the current study, the early growth response factor Egr-1 (26) (also called Zif/268(24) , NGF1-A(27) , Krox 24(28, 29) , TIS(30) , and CEF5 ((31) ; for Egr-1 review see (32) ) and the transcription factor Sp1(33) . Because many of these transcription factors belong to families consisting of multiple members, we suggested that there are several, possibly overlapping, multiprotein configurations of the fully assembled enhancer(10) . According to this scheme, a dynamic state of the functional enhancer complex and its capacity to assimilate signals transduced by individual family members are also implicit. Factor exchange is predicted to involve disruption of pre-existing protein-DNA and protein-protein contacts. Therefore, we further suggested that this process may entail binding of ARP-1 to site A, which results in formation of transient, transcriptionally inert complexes susceptible to modulation by the incoming factor(8, 9) .

Egr-1 activation of the apoAI gene displays no dependence upon enhancer modules other than sites E1 and E2. Furthermore, Egr-1 can efficiently overcome ARP-1-mediated repression, and activation by Egr-1 is not dependent upon prior repression by ARP-1. It therefore appears that Egr-1 is essentially insensitive to the transcription factor configuration of the apoAI enhancer and is consequently optimally suited to function as a device for overriding apoAI transcriptional controls in special situations (see below).

The apparent dispensability of Egr-1-responsive sites E1 and E2 for constitutive enhancer function further reinforces the notion that they are contingent enhancer modules that can be mobilized only in selected situations such as during development or in periods of unusual stress (see below). This is reminiscent of LFA1 (HNF-4) binding to its cognate site in the -1-antitrypsin promoter where the factor is essential for the activity of this promoter in HepG2 cells, fetal liver, and the yolk sac but not for expression in adult liver(34) . Similarly, HNF-4 binds to sites in the transthyretin gene promoter in vitro, although in vivo footprinting revealed that the same sites were vacant(35) . This implied that HNF-4 recruitment to its cognate site may also occur only under specialized circumstances.

Experiments designed to determine whether E1 and E2 are occupied by Egr-1 or other related factors in HepG2 cells revealed that site E1 is vacant while E2 is occupied by the transcription factor Sp1 (Fig. 2D). The E2 sequence is composed of extensively overlapping Egr-1 and Sp1 motifs, which suggests that Egr-1 and Sp-1 bind E2 in a mutually exclusive fashion. While this has not been formally proven for E2, a similar situation has been documented for a regulatory site nearly identical to E2 in the murine adenosine deaminase promoter(36) . However, in contrast to the E2 site where replacement of Sp1 by Egr-1 stimulates the activity of the apoAI promoter, replacement of Sp1 by Egr-1 in the context of the adenosine deaminase promoter results in transcriptional repression(36) , exemplifying that the capacity of Egr-1 to function as an activator or repressor is dependent upon the gene promoter and cell-type contexts(37) . A single nucleotide substitution in E2 that abolishes its ability to bind either Egr-1 or Sp1 has little impact on the basal activity of the apoAI enhancer in HepG2 cells, although it reduces its responsiveness to Egr-1. Thus, although Sp1 binding to E2 contributes very little to the overall transcriptional activity of the apoAI promoter in HepG2 cells, it is tempting to speculate that it may also represent a contingency mechanism required for some hitherto unidentified mode of expression of the apoAI gene.

What physiological conditions would lead to recruitment of Egr-1 to the apoAI enhancer? Egr-1 control of the apoAI enhancer obviously reflects some specialized program that is not called upon during routine circumstances. Egr-1 was originally defined as a gene whose expression is induced in response to mitogenic signals in all mammalian cells tested(26, 30, 38, 39, 40, 41, 42, 43) as well as regenerating hepatocytes in partially hepatectomized animals(39, 44, 45, 46) . Recent evidence suggests that Egr-1 is an important effector for the start of cell differentiation(47, 48) . It is also involved in restricting the development of monocyte precursors along the macrophage lineage(49) . Furthermore, since Egr-1 is expressed in murine peritoneal macrophages (50) and mature human myeloid leukemic (51) and cardiac cells(52) , it may play additional roles in more terminally differentiated cells(49) . However, with the exception of its early induction during hepatocyte proliferation following partial hepatectomy, Egr-1 has not been implicated in any signaling cascades regulating the behavior of mature hepatocytes. Our data predict that induction of Egr-1 in mature hepatocytes could reprogram the transcriptional apparatus of the apoAI gene (or other genes) leading to appropriate alterations in gene expression that result in sustained production of apoAI. It is therefore interesting that during liver regeneration, apoAI gene transcription remains nearly unchanged (53) despite major alterations in the levels of transcription factors involved in apoAI gene regulation(13, 54) . Together with our current results, this suggests that under these conditions, Egr-1 takes over apoAI gene regulation by overriding previously imposed transcriptional constraints. This implies that apoAI may play an as-yet unknown role in liver regeneration.

FOOTNOTES

*

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

Present address: Arthritis Center, Boston University School of Medicine, Boston, MA 02118.

¶

To whom correspondence should be addressed. Tel.: 914-732-4778; Fax: 914-732-5665.

()

The abbreviations used are: apoAI, apolipoprotein AI; HNF, hepatic nuclear factor; ARP-1, apolipoprotein regulatory protein-1; Egr, early growth response; CMV, cytomegalovirus; C/EBP, CAAT/enhancer binding protein; EMSA, electrophoretic mobility shift assay; CAT, chloramphenicol acetyltransferase.

()

E. Kilbourne, R. Widom, D. C. Harnish, S. Malik, and S. K. Karathanasis, unpublished results.

ACKNOWLEDGEMENTS

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