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PubMed1988

A DNA element responsible for the different tissue specificities of Friend and Moloney retroviral enhancers.

The transcriptional enhancers of the Moloney murine sarcoma virus (MuSV) and Moloney murine leukemia virus (MuLV) have different cell type specificities from that of the Friend MuLV. While the three enhancers are approximately equally active in erythroid cells, the Moloney MuSV and Moloney MuLV enhancers are 20- to 40-fold more active than the Friend MuLV enhancer in T-lymphoid cells. Using mutant enhancers, we have shown that specific differences between the nucleotide sequences of the Moloney MuSV and Friend MuLV enhancers are responsible for their different activities in T cells. Our data allow the localization of a DNA element, repeated several times within the enhancer, which modulates the activity of the enhancer in T cells without affecting it in erythroid cells. This element therefore appears to be one of the determinants of the tissue specificity of the enhancer.

Base Sequence↗

PubMed1988

Localization and footprinting of an enhancer within the avian sarcoma virus gag gene.

A cis-acting regulatory element within the gag gene of avian retroviruses has been localized by deletion analysis, and sites of protein interaction have been studied by DNase I footprinting. Unidirectional deletions were made from both the 5' and 3' ends of a 656-base-pair fragment of the gag gene of Fujinami sarcoma virus. These deletion mutants were tested for enhancer activity in a chloramphenicol acetyltransferase transient expression assay. A sharp 5' boundary for enhancer activity was observed between 776 and 786 nucleotides downstream from the transcription initiation site. In contrast, deletion from the 3' side resulted in a gradual loss of enhancer activity, reaching a near basal level of activity by nucleotide 868. Internal deletion of 76 nucleotides just downstream of the 5' boundary abolished enhancement. Mutagenesis of a consensus enhancer core sequence (GTGGTTTG) showed that this sequence was not necessary for enhancer activity in our transient assays. DNase I footprinting with both a highly purified enhancer-binding protein from rat liver (EBP20) and a partially purified chicken liver nuclear extract showed specific protection of nucleotides 813 to 872 within the localized enhancer region. Footprinting of unidirectional deletion mutants that had lost activity indicated that this binding was not sufficient to confer enhancement.

Animals↗

PubMed1989

An element of the BK virus enhancer required for DNA replication.

The human papovavirus BK virus contains three 68-base-pair (bp) repeats that act as transcriptional enhancers. An analysis of plasmids containing the BK virus origin revealed that sequences within the 68-bp enhancer are required for DNA replication as well as transcription of the early promoter in COS-1 cells. Origins with a single 68-bp repeat replicated as efficiently as did those with three repeats when transfected into COS-1 cells. Replication did not occur in the absence of enhancer sequences and could not be restored by distal placement of enhancers to enhancerless origins. However, as with simian virus 40, replication in vitro was not dependent on the presence of any enhancer sequences. Deletion analysis showed that replication of BK virus origins was dependent on the presence of the first 21 bp of the enhancer contiguous with the A-T-rich stretch of the origin. This 21-bp element is referred to as the rep element. Although in combination with rep the remaining 47 bp of the enhancer appear to increase replication by two- to fivefold, they alone are not sufficient to support replication. Deletions or insertions in the enhancer which did not alter the rep element had no major effect on replication. Site-directed mutagenesis of the Sp1-like site within the rep element, the NF1 site present in the enhancer, or the NF1 site in adjacent late-side sequences each reduced transcription by two- to fivefold, but had no effect on replication, suggesting that replication and transcription can be uncoupled.

BK Virus↗

PubMed1992

Repression of liver-specific hepatitis B virus enhancer 2 activity by adenovirus E1A proteins.

Two regions of the hepatitis B virus (HBV) genome have been shown to display properties of a transcriptional enhancer. Enhancer 1 is active in most hepatoma lines examined as well as in some non-hepatocyte-derived cell lines. In contrast, enhancer 2 activity is strictly liver specific. In this study, we show that adenovirus E1A expression in the highly differentiated human hepatoma line Huh6 strongly inhibits HBV enhancer 2-stimulated transcription while having no effect on HBV enhancer 1 activity. A sequence motif in HBV enhancer 2 which is essential for its enhancer function is the target for E1A-mediated repression. The repression of HBV enhancer 2 activity is mediated through the N-terminal region of the E1A proteins known to bind a 300-kDa cellular protein. Our results suggest that HBV enhancer function may be modulated by a cellular mechanism similar to E1A-mediated transcriptional repression.

Adenovirus E1A Proteins↗

PubMed1994

Complex functional interactions at the early enhancer of the PQ strain of BK virus.

BK virus is a human papovavirus that latently infects a majority of the world's population. There are more than 30 strains of the virus, most of which differ in the structure of the early enhancer region. The enhancer of the progenitor strain, WW, from which the other strains can be derived, consists of four conserved DNA domains, P, Q, R, and S. Rearrangement of the enhancer occurs upon passage in tissue culture and is thought to occur during virus replication. The strain under study, PQ, was selected upon passage of the Gardner strain (PPPQS) in the permissive cell line, Vero. Mutational analysis of the entire enhancer region demonstrates the importance of five cis-acting sequences: DNA sites B, C, and F, which have homology to the NF-1 protein binding sequence; one purine-rich motif designated A; and site D, which is similar to an SP-1 protein binding site. Two sites, B and C, appear to have a negative influence on gene activity. To study the functional interactions in more detail, promoter-enhancer constructions that contain different combinations of the five DNA sites linked to the chloramphenicol acetyltransferase gene were tested for early gene activity. The results reveal that the proteins binding to the enhancer functionally cooperate with each other. The effects of making mutations at the DNA sites are very similar to the effects of using excess enhancer DNA sequences to titrate the proteins that bind to the cis-acting DNA sites (in vivo competition). Moreover, the effects of changing the spacing between the DNA sites also demonstrate that there are cooperative interactions among the proteins that bind to the PQ strain enhancer. DNA sites B, C, and F are clearly protected from DNase I digestion by Vero cell nuclear proteins. In addition, mutation of each DNA site alters its sensitivity to DNase I in the presence of Vero cell proteins. Interestingly, mutation of site B affects protein binding to site B as well as to sites A, C, D, and F. These results suggest that cooperative functional and physical interactions occur at the early enhancer of the PQ strain.

Animals↗

PubMed1995

Transactivation of the Moloney murine leukemia virus and T-cell receptor beta-chain enhancers by cbf and ets requires intact binding sites for both proteins.

The Moloney murine leukemia virus (Mo-MLV) enhancer contains binding sites (LVb and LVc) for the ets gene family of proteins and a core site that binds the polyomavirus enhancer-binding protein 2/core-binding factor (cbf) family of proteins. The LVb and core sites in the Mo-MLV enhancer contribute to its constitutive activity in T cells. All three binding sites (LVb, LVc, and core) are required for phorbol ester inducibility of the Mo-MLV enhancer. Adjacent binding sites for the ets and cbf proteins likewise constitute a phorbol ester response element within the human T-cell receptor beta-chain (TCR beta) enhancer and contribute to constitutive transcriptional activity of the TCR beta enhancer in T cells. Here we show that the CBF alpha subunit encoded by the mouse Cbfa2 gene (the murine homolog of human AML1) and three ets proteins, Ets-1, Ets-2, and GA-binding protein (GABP), transactivate both the Mo-MLV and mouse TCR beta enhancer in transient-expression assays. Moreover, we show that transactivation by Cbf alpha 2 requires both intact ets and cbf binding sites. Transactivation by Ets-1, Ets-2, and GABP likewise requires intact binding sites for ets proteins and CBF. Supportive biochemical analyses demonstrate that both proteins can bind simultaneously to a composite enhancer element. These findings suggest that ets and cbf proteins cooperate in vivo to regulate transcription from the Mo-MLV and TCR beta enhancers.

Animals↗

PubMed1990

Involvement of a second lymphoid-specific enhancer element in the regulation of immunoglobulin heavy-chain gene expression.

To determine whether enhancer elements in addition to the highly conserved octamer (OCTA)-nucleotide motif are important for lymphoid-specific expression of the immunoglobulin heavy-chain (IgH) gene, we have investigated the effect of mutating the binding site for a putative additional lymphoid-specific transcription factor, designated NF-microB, in the murine IgH enhancer. We demonstrate that the NF-microB-binding site plays a critical role in the IgH enhancer, because mutation of the microB DNA motif decreased transcriptional activity of the IgH enhancer in cells of the B-cell lineage but not in nonlymphoid cells. This effect was comparable to or even stronger than the effect of a mutation in the OCTA site. Moreover, combined mutation of both microB and OCTA sites further reduced enhancer activity in lymphoid cells. Interestingly, alteration of either the microB or E3 site in a 70-base-pair fragment of the IgH enhancer that lacks the binding site for OCTA abolished enhancer activity in lymphoid cells completely. Nevertheless, a multimer of the microB motif alone showed no enhancer activity. DNase footprinting analysis corroborated the functional data showing that a lymphoid-specific protein binds to the microB DNA motif. Our results suggest that the microB element is a new crucial element important for lymphoid-specific expression of the IgH gene but that interaction with another enhancer element is essential for its activity.

Animals↗

PubMed1991

Positive and negative regulation of immunoglobulin gene expression by a novel B-cell-specific enhancer element.

A new B-cell-specific enhancer element has been identified 3' of E4 and the octamerlike motifs in the human immunoglobulin heavy-chain gene enhancer. Tandem copies of this 67-bp MnlI-AluI fragment, when fused to the chloramphenicol acetyltransferase gene driven by the conalbumin promoter, stimulated transcription in B cells but not in Jurkat T cells or HeLa cells. Footprinting analysis revealed that the identical sequence CCGAAACTGAAAAGG, designated E6, was protected by nuclear extracts from B cells, T cells, or HeLa cells. Gel mobility shift assays using a synthetic E6 motif detected a B-cell-specific complex in addition to a ubiquitous band found also in T cells and HeLa cells. In agreement with the results of gel retardation assays, tandem copies of the E6 motif stimulated transcription in ARH77 and Raji cells but not in Jurkat or HeLa cells. Furthermore, a mutant E6 motif lost both in vitro binding activity and in vivo enhancer activity. In striking contrast to the mouse Ig heavy-chain enhancer, in which the octamer motif acts as a B-cell-specific enhancer element, the human enhancer contains an octamerlike sequence with one base substitution which bound octamer-binding proteins with only very low affinity and showed no enhancer activity of its own. Interestingly, the MnlI-AluI fragment could suppress the basal-level activity of the conalbumin promoter in both Jurkat and HeLa cells. Moreover, simian virus 40 enhancer activity was blocked by the MnlI-AluI fragment in HeLa cells but not in B cells. Thus, the novel enhancer element identified in this study is probably a target site for both positive and negative factors.

B-Lymphocytes↗

PubMed1992

Cooperative binding of the Xenopus RNA polymerase I transcription factor xUBF to repetitive ribosomal gene enhancers.

Upstream binding factor (UBF) is a DNA-binding transcription factor implicated in ribosomal gene promoter and enhancer function in vertebrates. UBF is unusual in that it has multiple DNA-binding domains with homology to high-mobility-group (HMG) nonhistone chromosomal proteins 1 and 2. However, a recognizable DNA consensus sequence for UBF binding is lacking. In this study, we have used gel retardation and DNase I footprinting to examine Xenopus UBF (xUBF) binding to Xenopus laevis ribosomal gene enhancers. We show that UBF has a minimum requirement for about 60 bp of DNA, the size of the short enhancer variant in X. laevis. Stronger UBF binding occurs on the longer enhancer variant (81 bp) and on multiple enhancers linked head to tail. In vivo, Xenopus ribosomal gene enhancers exist in blocks of 10 alternating 60- and 81-bp repeats within the intergenic spacer. In vitro, UBF binds cooperatively to probes with 10 enhancers, with five intermediate complexes observed in titration experiments. This suggests that, on average, one UBF dimer binds every two enhancers. A single UBF dimer can produce a DNase I footprint ranging in size from approximately 30 to about 115 bp on enhancer probes of different lengths. This observation is consistent with the hypothesis that multiple DNA-binding domains or subdomains within UBF bind independently, forming more-stable interactions on longer probes.

Animals↗

PubMed1992

Characterization of the human immunoglobulin kappa gene 3' enhancer: functional importance of three motifs that demonstrate B-cell-specific in vivo footprints.

Using a combination of in vivo footprinting and site-directed mutagenesis, we have functionally characterized an enhancer located 12 kb downstream of the human immunoglobulin kappa constant-region gene. The core enhancer region is highly homologous to the murine 3' kappa enhancer. However, in addition to two regulatory elements homologous to the functional motifs of the murine enhancer, we find a third positive regulatory element in the human enhancer. This element is associated with an 11/12-bp direct repeat (DR) that is well conserved in the murine locus but was not recognized as functionally important in the murine enhancer. Mutation of any of the three motifs of the human enhancer decreases its activity to 3 to 20% of the wild-type level, indicating cooperative interaction between these elements. The DR motif does not resemble any known enhancer element and does not appear to function as a transcriptional activator on its own when present in multiple copies. Interestingly, nuclear extracts from both B- and T-cell lines contain factors binding to DR in vitro, but in vivo footprinting shows no evidence of protein-DNA binding in the T-cell line. This finding suggests that an additional regulatory mechanism, such as the effect of chromatin configuration on accessibility, may be involved in the B-cell-restricted activity of the human 3' kappa enhancer.

B-Lymphocytes↗

PubMed1992

The polyomavirus enhancer activates chromatin accessibility on integration into the HPRT gene.

Recent studies suggest that enhancers may increase the accessibility of chromatin to transcription factors. To test the effects of a viral enhancer on chromatin accessibility, we have inserted minigenes with or without the polyomavirus enhancer into the third exon of the hypoxanthine phosphoribosyltransferase (HPRT) gene by homologous recombination and have prepared high-resolution maps of gene accessibility by using a novel polymerase chain reaction assay for DNase I sensitivity. In its native state, we find that the HPRT gene has low sensitivity to DNase I in fibrosarcoma cells. Insertion of the polyomavirus enhancer and neo reporter gene into exon 3 confers altered HPRT DNase I sensitivity for several kilobases on either side of the enhancer. The changes in DNase I sensitivity peak near the enhancer and decline with distance from the enhancer. The increase in HPRT DNase I sensitivity persisted when the tk promoter was deleted from the inserted construct but disappeared when the enhancer was deleted. These experiments identify the polyomavirus enhancer as a cis-acting initiator of chromatin accessibility.

Base Sequence↗

PubMed1993

In vitro definition of the yeast RNA polymerase I enhancer.

In vitro conditions are reported under which an EcoRI-HpaI fragment of the Saccharomyces cerevisiae ribosomal gene spacer will enhance transcription from an adjacent RNA polymerase I promoter. Enhancement is largely independent of orientation and distance and is proportional to copy number. Mapping experiments reveal that two separate regions of the EcoRI-HpaI fragment are independently capable of promoter stimulation. These regions appear to correspond to elements which have been shown by previous workers to cause enhancement in vivo. Using the detergent Sarkosyl to limit the number of rounds of transcription from each promoter, we found that the degree of enhancement is similar whether one or many rounds of transcription occur. This finding supports a model in which the enhancer increases the number of stable promoter complexes but does not alter the loading of polymerase on an active promoter. Once the stable promoter complex is formed, the enhancer can be physically severed from the promoter with no loss of enhancement. Likewise, the upstream activation region of the promoter can be severed from the core promoter domain once the stable complex has been formed. These results are interpreted to mean that the enhancer functions only to assist stable complex formation and, once that is accomplished, the enhancer is dispensable.

Base Sequence↗

PubMed1993

Transcription of the histone H5 gene is regulated by three differentiation-specific enhancers.

Histone H5, an early marker of the avian erythroid lineage, is expressed at low levels in early erythroid precursors and at higher levels in more mature cells. We show that the increase in H5 expression is due to transcriptional activation of the H5 gene following differentiation of precursor CFU(E). We have found and characterized two upstream enhancers, E1 (between -2233 and -1878 from the site of transcription initiation, +1) and E3 (between -1321 and -1163), and confirmed the presence of a downstream enhancer (C. D. Trainor, S. J. Stamler, and J. D. Engel, Nature [London] 328:827-830, 1987) E7 (between +846 and +1181) which are responsible for the increase in H5 gene transcription. The enhancers had a weak effect in nondifferentiated CFU(E) but a strong effect when the cells were induced to differentiate. Cooperation among the three enhancers, however, was not required for H5 gene activity in the differentiated cells. The enhancers contain binding sites for several ubiquitous and erythroid cell-specific nuclear proteins, including GATA-1, as demonstrated with GATA-1-specific antibodies. Although the GATA sites were required for enhancer function, the concentration of GATA-1, GATA-2, and GATA-3 decreased during cell differentiation, and overexpression of these factors had little effect on H5 transcription. Hence, the differentiation-specific effect of the enhancers is not mediated by changes in relative levels of the GATA factors. Functional analysis of the H5 promoter indicated that the requirement of several elements, including a GC box necessary for transcription enhancement, did not change during the early stages of CFU(E) differentiation. However, the UPE, a positive element in proliferating CFU(E) recognized by the transcription factor H4TF2, was dispensable in the differentiated cells. These results suggest that as the cells enter the final stages of differentiation, there is a reprogramming of the regulatory factors that control H5 transcription and that the enhancers rescue and increase the activity of the promoter.

Amino Acid Sequence↗

PubMed1993

Multiple proteins interact with the fushi tarazu proximal enhancer.

The expression of the Drosophila segmentation gene fushi tarazu (ftz) is controlled at the level of transcription. The proximal enhancer, located approximately 3.4 kb upstream of the transcription start site, directs lacZ fusion gene expression in a ftz-like seven-stripe pattern in transgenic fly embryos. We have taken a biochemical approach to identify DNA-binding proteins that regulate ftz gene expression through the proximal enhancer. DNase I footprinting and methylation interference experiments with staged Drosophila embryo nuclear extracts identified nine protein binding sites in the proximal enhancer. Ten different sequence-specific DNA-binding complexes that interact with eight of these sites were identified. Some interact with multiple sites, while others bind to single sites in the enhancer. Two of the complexes that interact with multiple sites appear to contain the previously described ftz regulators, FTZ-F1 and TTK/FTZ-F2. These in vitro studies allowed us to narrow down the proximal enhancer to a 323-bp DNA fragment that contains all of the protein binding sites. Expression directed by this minimal enhancer element in seven ftz-like stripes in transgenic embryos is identical to that directed by the full-length enhancer. Internal deletions of several sites abolish reporter gene expression in vivo. Thus, the ftz proximal enhancer, like other cell-type-specific eukaryotic enhancers, interacts with an array of proteins that are expected to mediate the establishment, maintenance, and repression of transcription of the ftz gene in seven stripes in the developing embryo.

Animals↗

PubMed1994

Suppression of albumin enhancer activity by H-ras and AP-1 in hepatocyte cell lines.

We demonstrated, using a transient transfection assay, that the albumin enhancer increased the expression of the albumin promoter in a highly differentiated, simian virus 40 (SV40)-immortalized hepatocyte cell line, CWSV1, but was not functional in two ras-transformed cell lines (NR3 and NR4) derived from CWSV1 by stable transfection with the T24ras oncogene. A transient cotransfection assay showed that T24ras and normal c-Ha-ras were each able to inhibit the activity of the albumin enhancer in an immortal hepatocyte cell line. DNase I footprinting and gel mobility shift assays demonstrated that the DNA binding activities specific to the albumin enhancer were not decreased in the ras-transformed cells. ras also did not diminish the expression of HNF1 alpha, C/EBP alpha, HNF3 alpha, HNF3 beta, or HNF3 gamma but did significantly increase AP-1 binding activity. Three AP-1 binding sites were identified within the albumin enhancer, and DNA binding activities specific to these AP-1 sites were induced in the ras-transformed hepatocytes. Subsequent functional assays showed that overexpression of c-jun and c-fos inhibited the activity of the albumin enhancer. Site-directed mutagenesis of the AP-1 binding sites in the albumin enhancer partially abrogated the suppressing effect of ras and c-jun/c-fos on the enhancer. These functional studies therefore supported the results of the structural studies with AP-1. We conclude that the activity of the albumin enhancer is subject to regulation by ras signaling pathways and that the effect of ras on the albumin enhancer activity may be mediated by AP-1.

Animals↗

PubMed1995

Individual mouse alpha-fetoprotein enhancer elements exhibit different patterns of tissue-specific and hepatic position-dependent activities.

Transcription of the mouse alpha-fetoprotein (AFP) gene, which is expressed at high levels in the visceral endoderm of the yolk sac and fetal liver and at low levels in the fetal gut, is regulated by three distinct upstream enhancer regions. To investigate the activities of these regions, each enhancer was individually linked to a heterologous human beta-globin promoter fused to the mouse class I H-2Dd structural gene. When tested in transgenic mice, the beta-globin promoter alone has minimal activity. We find that all three enhancers activate the beta-globin promoter in an AFP-like pattern; i.e., activity is detected in the yolk sac, fetal liver, and fetal gut. The enhancers remain active in the livers and guts of adult mice, consistent with previous studies showing that postnatal AFP repression is due not to the loss of enhancer activity but to a dominant repressor region. Enhancer III also functions in the brain. In addition, these studies reveal that the three enhancers exhibit different position-dependent activities in the adult liver. Enhancers I and II are most active in hepatocytes surrounding the central vein, with a gradual decrease in activity along the hepatic plates toward the portal triad. Enhancer III is active exclusively in hepatocytes surrounding the central vein. These data represent the first examples of individual control elements exhibiting positionally regulated activity in adult liver.

Animals↗

PubMed1997

SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene.

The identification of mutations in the SRY-related SOX9 gene in patients with campomelic dysplasia, a severe skeletal malformation syndrome, and the abundant expression of Sox9 in mouse chondroprogenitor cells and fully differentiated chondrocytes during embryonic development have suggested the hypothesis that SOX9 might play a role in chondrogenesis. Our previous experiments with the gene (Col2a1) for collagen II, an early and abundant marker of chondrocyte differentiation, identified a minimal DNA element in intron 1 which directs chondrocyte-specific expression in transgenic mice. This element is also a strong chondrocyte-specific enhancer in transient transfection experiments. We show here that Col2a1 expression is closely correlated with high levels of SOX9 RNA and protein in chondrocytes. Our experiments indicate that the minimal Col2a1 enhancer is a direct target for Sox9. Indeed, SOX9 binds to a sequence of the minimal Col2a1 enhancer that is essential for activity in chondrocytes, and SOX9 acts as a potent activator of this enhancer in cotransfection experiments in nonchondrocytic cells. Mutations in the enhancer that prevent binding of SOX9 abolish enhancer activity in chondrocytes and suppress enhancer activation by SOX9 in nonchondrocytic cells. Other SOX family members are ineffective. Expression of a truncated SOX9 protein lacking the transactivation domain but retaining DNA-binding activity interferes with enhancer activation by full-length SOX9 in fibroblasts and inhibits enhancer activity in chondrocytes. Our results strongly suggest a model whereby SOX9 is involved in the control of the cell-specific activation of COL2A1 in chondrocytes, an essential component of the differentiation program of these cells. We speculate that in campomelic dysplasia a decrease in SOX9 activity would inhibit production of collagen II, and eventually other cartilage matrix proteins, leading to major skeletal anomalies.

3T3 Cells↗

PubMed2003

Enhancer sequences influence the role of the amino-terminal domain of bicoid in transcription.

Bicoid (Bcd) is a Drosophila melanogaster morphogenetic gradient that controls embryonic patterning by activating target gene expression in a concentration-dependent manner. In this study we describe experiments to determine how different enhancers respond to Bcd distinctively, focusing on two natural Bcd-responsive enhancer elements, hunchback (hb) and knirps (kni). Our results show that, on the hb enhancer element, the amino-terminal domain of Bcd (residues 1 to 91) plays primarily an inhibitory role, whereas on the kni enhancer element this same Bcd domain plays a positive role at low protein concentrations. We further demonstrate that while the amino-terminal domain is largely dispensable for cooperative binding to the hb enhancer element, it is preferentially required for cooperative binding to the kni enhancer element. Alteration of the arrangement of Bcd binding sites in the kni enhancer element reduces the role of the amino-terminal domain in cooperative DNA binding but increases the effectiveness of the self-inhibitory function. In addition, elimination of symmetric pairs of Bcd binding sites in the kni enhancer element reduces both DNA binding and activation by Bcd. We propose that the amino-terminal domain of Bcd is an enhancer-specific switch that contributes to the protein's ability to activate different target genes in distinct manners.

Animals↗