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PubMed2002

GAGA can mediate enhancer function in trans by linking two separate DNA molecules.

Enhancers have been defined as cis-acting DNA sequences that stimulate transcription from a linked promoter in a distance- and orientation-independent manner. How enhancers activate gene transcription over vast chromosomal distances within metazoan genomes remains poorly understood. Here, we show that the transcription factor GAGA can stimulate transcription by linking an enhancer to its cognate promoter. Strikingly, in addition to facilitating activation by a remote enhancer in cis, GAGA can direct activation of a promoter by an enhancer located on a separate DNA molecule. Enhancer function in trans is critically dependent on POZ domain-mediated GAGA oligomerization, enabling GAGA to bind two DNA molecules simultaneously. Transcriptional activation by an enhancer functioning in trans was observed both in transfected cells and in reconstituted transcription reactions. We propose that GAGA facilitates long-range activation by providing a protein bridge that mediates enhancer-promoter communication.

Animals↗

PubMed2003

Thyroid hormone-regulated enhancer blocking: cooperation of CTCF and thyroid hormone receptor.

The highly conserved, ubiquitously expressed, zinc finger protein CTCF is involved in enhancer blocking, a mechanism crucial for shielding genes from illegitimate enhancer effects. Interestingly, CTCF-binding sites are often flanked by thyroid hormone response elements (TREs), as at the chicken lysozyme upstream silencer. Here we identify a similar composite site positioned upstream of the human c-myc gene. For both elements, we demonstrate that thyroid hormone abrogates enhancer blocking. Relief of enhancer blocking occurs even though CTCF remains bound to the lysozyme chromatin. Furthermore, chromatin immunoprecipitation analysis of the lysozyme upstream region revealed that histone H4 is acetylated at the CTCF-binding site. Loss of enhancer blocking by the addition of T3 led to increased histone acetylation, not only at the CTCF site, but also at the enhancer and the promoter. Thus, when TREs are adjacent to CTCF-binding sites, thyroid hormone can regulate enhancer blocking, thereby providing a new property for what was previously thought to be constitutive enhancer shielding by CTCF.

Acetylation↗

PubMed1992

Molecular analysis of the zeste-white interaction reveals a promoter-proximal element essential for distant enhancer-promoter communication.

We have analyzed the eye and testis enhancers located 1 kb upstream of the transcription start site of the white gene. Both enhancers confer the corresponding tissue-specific expression on a heterologous promoter as well as on the white promoter. The eye determinant consists of multiple elements, each able to stimulate eye-specific expression. It also contains five binding sites for the zeste protein while the immediately adjacent testis element contains none. Site-directed mutation of these zeste binding sites abolishes the zeste-white interaction but does not significantly affect the eye enhancer activity, indicating that they are not important for the eye enhancer activity per se. Other zeste binding sites just upstream of the promoter are not necessary for the zeste-white interaction. We conclude that the overlap of the eye enhancer with the zeste binding sites is responsible for the zeste-white interaction and explains why this interaction affects eye but not testis expression. Sequence deletion or substitution experiments suggested that the white promoter is internal to the transcription start site; the zeste protein is not required for distant enhancer action but a 95-bp promoter-proximal sequence is essential for distant enhancer-promoter interaction. This element may serve as an anchor to stabilize formation of a loop that brings the enhancer to the vicinity of the promoter.

Animals↗

PubMed1998

The effects of E mu, 3'alpha (hs 1,2) and 3'kappa enhancers on mutation of an Ig-VDJ-Cgamma2a Ig heavy gene in cultured B cells.

The Ig kappa intronic and 3'kappa light chain enhancers have been shown to be necessary for V region hypermutation in kappa light chain transgenes. To investigate the role of the E mu intronic enhancer in V region hypermutation of heavy chain genes, E mu and its associated matrix attachment regions (MAR) were replaced with the SV40 or the cytomegalovirus (CMV) enhancer in a gamma2a construct that hypermutates its rearranged VDJ region in the NSO plasmacytoma and 18.81 pre-B cell lines. In this model in vitro system, mutation rates of stable transfectants were determined by reversion analysis using a V region stop codon that, when mutated, allowed the detection of cellular revertants by ELISA spot assay. The gamma2a constructs with the E mu, SV40 and CMV enhancers mutated at comparably high rates in the B cell lines, but not in L cells, indicating that the E mu enhancer and its associated MAR were not specifically required for IgH hypermutation in this system. In parallel experiments, the addition of the 3'alpha heavy chain enhancer (hs 1,2) or the 3'kappa light chain enhancer did not increase the mutation rate of a related mu reporter construct in which the associated VDJ mutates at a moderately low rate in NSO cells or in cell hybrids made between 18.81 and NSO. These results imply that cis-acting IgH elements that promote hypermutation may not be restricted to Ig-specific transcriptional enhancers.

Animals↗

PubMed1987

A cellular protein binds to a conserved sequence in the adenovirus type 2 enhancer.

A sensitive gel retention assay has been utilized to detect proteins from uninfected Hela nuclei which interact with the adenovirus type 2 enhancer. This assay has been employed to monitor fractionation of nuclear extracts. Three enhancer binding factors were resolved by chromatography on DEAE-Sepharose and one of the factors was further purified by chromatography on heparin-Sepharose. DNase protection experiments have shown that the heparin-Sepharose fraction contains a factor which binds predominantly to the conserved sequence GTGGAAATTT present at position 160 in the adenovirus type 2 genome and found in many viral and cellular enhancers. Protection of this sequence from DNase I digestion was abolished by competition with a synthetic duplex oligonucleotide spanning bases 144-181. This region corresponds to the sequence defined by Hen et al. as possessing enhancer function. Competition experiments indicated that the enhancer binding factor also bound, albeit with reduced affinity, to multiple sites in the Ela upstream region located between positions 192 and 353. Within the sequences which compete are regions with homology to the high affinity site at position 160. The enhancer binding factor also binds with high affinity to sequences within the SV40 enhancer demonstrating that this factor interacts with sequences common to both the adenovirus and SV40 enhancers.

Adenoviruses, Human↗

PubMed1989

Differential activation of the 21-base-pair enhancer element of human T-cell leukemia virus type I by its own trans-activator and cyclic AMP.

A transcriptional trans-acting factor p40tax of human T-cell leukemia virus type I (HTLV-I) functions as an inducer for expression of HTLV-I provirus via activation of the enhancer in the long terminal repeat of HTLV-I. In addition to p40tax and a tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C, we report here that forskolin, an activator of adenyl cyclase, also induces function of the HTLV-I enhancer. Experiments with mutants of the HTLV-I enhancer revealed that TPA-induced activation was not mediated by solely a 21-base-pair (bp) sequence that is repeated three times in the enhancer, whereas the 21-bp enhancer element can act as a sufficient cis-acting sequence for activation by both p40tax and forskolin. In addition, we found that nuclear factor(s) like the cyclic AMP-responsive element (CRE) binding factor could bind to the HTLV-I 21-bp enhancer element. However, a difference was found in sequences required for activation by p40tax and forskolin. A CRE related sequence present in the 21-bp enhancer element was enough for forskolin-induced activation. On the other hand, p40tax required a much longer sequence that is overlapping but not identical to the CRE related sequence, suggesting that the forskolin-induced cyclic AMP pathway may be partly involved in, but not sufficient for p40tax-mediating trans-activation of the HTLV-I enhancer.

Base Composition↗

PubMed1993

A promoter-linked coupling region required for stimulation of alpha-fetoprotein transcription by distant enhancers.

We previously demonstrated that the rat alpha-fetoprotein (AFP) gene has three upstream enhancers that stimulate the AFP promoter additively in HepG2 cells (1). In this paper, deletion analysis demonstrated that a promoter-linked segment from -178 to -155 was required for full activity when the enhancers were distant from the promoter, even at less than their normal genomic distances, but dispensable when the enhancers were moved close to the promoter. This 'promoter-coupling element' appears to interact simultaneously with all three enhancers. Deletion analysis also localized a transcription stimulatory and a negative region in the promoter. Though these latter regions controlled the strength of the isolated promoter, they did not affect 'coupling' to the distant enhancers, and transcription stimulation by these distal promoter elements was small compared to the distant enhancers. Overall, the distant enhancers, acting through the promoter-coupling element, accounted for 70% of the activity of the transfected AFP gene. Footprint analysis with HepG2 nuclear extracts demonstrated protein binding at two sites near the promoter-coupling element. The data indicate a positive transcription control mechanism by which distant enhancers stimulate the AFP promoter through a specific promoter-linked element.

Animals↗

PubMed1998

Dimerization and HMG box domains 1-3 present in Xenopus UBF are sufficient for its role in transcriptional enhancement.

Transcription of Xenopus ribosomal genes by RNA polymerase I is directed by a stable transcription complex that forms on the gene promoter. This complex is comprised of the HMG box factor UBF and the TBP-containing complex Rib1. Repeated sequence elements found upstream of the ribosomal gene promoter act as RNA polymerase I-specific trans-criptional enhancers. These enhancers function by increasing the probability of a stable transcription complex forming on the adjacent promoter. UBF is required for enhancer function. This role in enhancement is distinct from that at the promoter and does not involve translocation of UBF from enhancer repeats to the promoter. Here we utilize an in vitro system to demonstrate that a combination of the dimerization domain of UBF and HMG boxes 1-3 are sufficient to specify its role in enhancement. We also demonstrate that the acidic C-terminus of UBF is primarilyresponsible for its observed interaction with Rib1. Thus, we have uncoupled the Rib1 interaction and enhancer functions of UBF and can conclude that direct interaction with Rib1 is not a prerequisite for the enhancer function of UBF.

Animals↗

PubMed2000

HMG I/Y regulates long-range enhancer-dependent transcription on DNA and chromatin by changes in DNA topology.

The nature of nuclear structures that are required to confer transcriptional regulation by distal enhancers is unknown. We show that long-range enhancer-dependent beta-globin transcription is achieved in vitro upon addition of the DNA architectural protein HMG I/Y to affinity-enriched holo RNA polymerase II complexes. In this system, HMG I/Y represses promoter activity in the absence of an associated enhancer and strongly activates transcription in the presence of a distal enhancer. Importantly, nucleosome formation is neither necessary for long-range enhancer regulation in vitro nor sufficient without the addition of HMG I/Y. Thus, the modulation of DNA structure by HMG I/Y is a critical regulator of long-range enhancer function on both DNA and chromatin-assembled genes. Electron microscopic analysis reveals that HMG I/Y binds cooperatively to preferred DNA sites to generate distinct looped structures in the presence or absence of the beta-globin enhancer. The formation of DNA topologies that enable distal enhancers to strongly regulate gene expression is an intrinsic property of HMG I/Y and naked DNA.

Base Sequence↗

PubMed2001

Characterization of Sp1, AP-1, CBF and KRC binding sites and minisatellite DNA as functional elements of the metastasis-associated mts1/S100A4 gene intronic enhancer.

The mts1/S100A4 gene encodes a small acidic calcium-binding protein that is expressed in a cell-specific manner in development, tumorigenesis and certain tissues of adult mice. A composite enhancer that is active in murine mammary adenocarcinoma cells was previously identified in the first intron of the mts1/S100A4 gene. Here we present a detailed analysis of the structure and function of this enhancer in the Mts1/S100A4-expressing CSML100 and non-expressing CSML0 mouse adenocarcinoma cell lines. In CSML100 cells the enhancer activity is composed of at least six cis-elements interacting with Sp1 and AP-1 family members and CBF/AML/PEBP2 and KRC transcription factors. In addition, a minisatellite-like DNA sequence significantly contributes to the enhancer activity via interaction with abundant proteins, which likely have been described previously under the name minisatellite-binding proteins. Extensive mutational analysis of the mts1/S100A4 enhancer revealed a cooperative function of KRC and the factors binding minisatellite DNA. This is the first example of an enhancer where two nuclear factors earlier implicated in different recombination processes cooperate to activate transcription. In Mts1/S100A4-negative CSML0 cells the strength of the enhancer was 7- to 12.5-fold lower compared to that in CSML100 cells, when referred to the activities of three viral promoters. In CSML0 cells the enhancer could be activated by exogenous AP-1 and CBF transcription factors.

Allosteric Site↗

PubMed2004

CTCF-dependent enhancer blockers at the upstream region of the chicken alpha-globin gene domain.

The eukaryotic genome is partitioned into chromatin domains containing coding and intergenic regions. Insulators have been suggested to play a role in establishing and maintaining chromatin domains. Here we describe the identification and characterization of two separable enhancer blocking elements located in the 5' flanking region of the chicken alpha-globin domain, 11-16 kb upstream of the embryonic alpha-type pi gene in a DNA fragment harboring a MAR (matrix attachment region) element and three DNase I hypersensitive sites (HSs). The most upstream enhancer blocking element co-localizes with the MAR element and an erythroid-specific HS. The second enhancer blocking element roughly co-localizes with a constitutive HS. The third erythroid-specific HS present within the DNA fragment studied harbors a silencing, but not an enhancer blocking, activity. The 11 zinc-finger CCCTC-binding factor (CTCF), which plays an essential role in enhancer blocking activity in many previously characterized vertebrate insulators, is found to bind the two alpha-globin enhancer blocking elements. Detailed analysis has demonstrated that mutation of the CTCF binding site within the most upstream enhancer blocking element abolishes the enhancer blocking activity. The results are discussed with respect to special features of the tissue-specific alpha-globin gene domain located in a permanently open chromatin area.

5' Flanking Region↗

PubMedDate not supplied

Specific enhancement of intra-abdominal abscesses with perfluoroctylbromide for CT imaging.

Perfluoroctylbromide (PFOB), a radiopaque reticuloendothelial system contrast media for computed tomography, has been shown to accumulate in macrophages. In the current study PFOB was tested in rabbits as an abscess imaging agent. Two abscesses were induced in each of 24 rabbits, one in the liver and the other in the peritoneal cavity. CT of the rabbit abdomen was performed four days later, two days after the administration of 5 gm/Kg of PFOB to 12 of these rabbits. The average enhancement of the wall of liver abscesses was by 140 Hounsfield units (HU) relative to the enhanced liver and peritoneal abscesses by 135 HU relative to the control group. This enhancement was secondary to the intense accumulation of PFOB filled macrophages in the abscess wall. In those rabbits where the liver abscess ruptured, the edges of the peritoneal collections enhanced by 147 HU. Regions of inflammation prior to liquifaction enhanced considerably. These areas could not be detected in the animals not receiving PFOB. Though the liquified center of liver abscesses could be seen in the absence of PFOB, none of the peritoneal abscesses could be detected in the animals not receiving PFOB. In contradistinction, all peritoneal abscesses enhanced considerably following PFOB allowing their prospective localization. In conclusion, PFOB accumulates in abscess walls and areas of inflammation producing marked CT enhancement of liver and peritoneal abscess collections. This enhancement allowed the differentiation of peritoneal abscess collections from adjacent bowel.

Abscess↗

PubMedDate not supplied

Clustered breast microcalcifications: evaluation by dynamic contrast-enhanced subtraction MRI.

OBJECTIVE: Our goal was to evaluate dynamic contrast-enhanced subtraction MRI in the diagnosis of isolated clustered calcifications of the breast. MATERIALS AND METHODS: One hundred seventy-two patients underwent surgical biopsy for isolated clustered breast calcifications. Their mammograms showed round (n = 88) or linear/irregular (n = 84) microcalcifications. All patients had a preoperative Gd-DOTA-enhanced subtraction dynamic study. Any early contrast enhancement in the breast parenchyma concomitant with early enhancement of normal vessels was considered positive. RESULTS: Fifty-eight in situ carcinomas, 22 invasive carcinomas, and 92 benign lesions were found at histological analysis. Dynamic MR sequences showed early contrast enhancement in 76 of 80 malignant lesions (sensitivity 95%) and in 45 of 92 benign lesions (specificity 51%). Two invasive and two intraductal carcinomas did not show early contrast enhancement. Three independent observers agreed in rating early contrast enhancement in 143 of 172 lesions. CONCLUSION: Poor specificity limits the diagnostic accuracy of dynamic contrast-enhanced subtraction MRI in distinguishing benign from malignant microcalcifications on mammography.

Adult↗

PubMedDate not supplied

Transient peritumoral enhancement during dynamic MRI of the liver: cavernous hemangioma versus hepatocellular carcinoma.

PURPOSE: The purpose of this work was to compare the incidence and pattern of transient peritumoral parenchymal enhancement for cavernous hemangioma and hepatocellular carcinoma during dynamic MRI of the liver. METHOD: Two hundred seven hemangiomas and 155 hepatocellular carcinomas up to 4 cm in size were retrospectively assessed. The peritumoral enhancement was comparatively analyzed in terms of the shape, extent, signal intensity, and dependence on the size and degree of contrast enhancement of each tumor. RESULTS: For small lesions (<2 cm), hemangiomas (16/141; 11.3%) showed a higher incidence (p = 0.026) of peritumoral enhancement than hepatocellular carcinomas (3/87; 3.5%). For larger lesions (2-4 cm), there was no significant difference (p > 0.05) in the incidence of peritumoral enhancement of hemangiomas (15/66; 22.7%) and hepatocellular carcinomas (15/68; 22.1%). Nineteen (61.3%) of the 31 hemangiomas showed contrast agent filling the entire tumor volume at the phase of peritumoral enhancement. CONCLUSION: In spite of the limited specificity, for a <2 cm small focal lesion with homogeneous contrast enhancement on early phase dynamic MR images in the liver, peritumoral enhancement could suggest a higher possibility of hemangioma rather than hepatocellular carcinoma.

Adult↗

PubMed1999

Pachymeningeal gadolinium enhancement of the lumbar region secondary to neuraxis hypotension.

STUDY DESIGN: A case of diffuse pachymeningeal gadolinium enhancement of the lumbar region secondary to neuraxis hypotension is presented. OBJECTIVE: To report a case of diffuse pachymeningeal gadolinium enhancement of the lumbar region and to show the importance of considering neuraxis hypotension in the differential diagnosis of this type of enhancement so as to avoid excessive invasive and noninvasive diagnostic testing. SUMMARY OF BACKGROUND DATA: Diffuse pachymeningeal gadolinium enhancement of the lumbar region secondary to neuraxis hypotension has not been reported previously. METHODS: A case of diffuse pachymeningeal gadolinium enhancement of the lumbar region is presented in the context of clinical signs and symptoms replete with a history of cerebrospinal fluid diversion that strongly suggest neuraxis hypotension. RESULTS: The patient's clinical presentation and history of shunting implicated neuraxis hypotension as a cause of the diffuse dural enhancement. CONCLUSION: Proper attribution of the dural gadolinium enhancement to neuraxis hypotension helped avoid a dural biopsy with its potential attendant morbidity. It is important to consider neuraxis hypotension in the differential diagnosis of diffuse pachymeningeal enhancement occurring anywhere in the central neuraxis to avoid unnecessary diagnostic testing with its attendant morbidity and cost.

Aged↗

PubMed2003

Contrast enhanced color Doppler endorectal sonography of prostate: efficiency for detecting peripheral zone tumors and role for biopsy procedure.

PURPOSE: We evaluated the accuracy of contrast enhanced color Doppler endorectal ultrasound to guide biopsy for the detection of prostate cancer. MATERIALS AND METHODS: A total of 85 patients were evaluated with gray scale and color Doppler before and during intravenous injection of ultrasound contrast agent made of galactose based air microbubbles. Our biopsy protocol was performed during contrast injection. An additional 18 directed cores were obtained based on contrast enhanced imaging. Diagnostic efficiency with and without contrast medium injection for detecting prostate cancer were compared based on biopsy results. RESULTS: Cancer was identified in a total of 58 biopsy sites in 54 patients. Gray scale imaging revealed 96 abnormal hypoechoic nodules or irregular zones inside the outer gland, of which 48 were malignant on pathological evaluation. Contrast enhanced color Doppler had higher sensitivity (93%) than unenhanced color Doppler (54%), while specificity increased only 79% to 87% for enhanced imaging. Nine of 10 isoechoic suspicious zones were depicted with enhancement, while unenhanced Doppler detected 7 of them. There was no significant difference between the intensity of enhancement and tumor Gleason scores. CONCLUSIONS: Contrast enhanced color Doppler endorectal sonography increases the detection of prostate cancer. Improvement in sensitivity was high, while the difference in specificity was not as pertinent. It is accurate when using a common and routine application ultrasound unit. This technique is easy to perform and not time-consuming. Obtaining additional biopsy cores of suspicious enhancing foci significantly improves the detection rate of cancer.

Aged↗

PubMed2005

Renal functional contrast-enhanced magnetic resonance imaging: evaluation of a new rapid-clearance blood pool agent (p792) in sprague-dawley rats.

OBJECTIVES: The objective of the present study was to compare P792, a new rapid clearance blood pool agent characterized by negligible interstitial diffusion but unrestricted glomerular filtration, with Gd-DOTA in both qualitative and quantitative aspects of renal functional magnetic resonance imaging. MATERIALS AND METHODS: Dynamic imaging was performed with a fast T1-weighted gradient-echo sequence on a 1.5-T magnet in 25 Sprague-Dawley rats, after injection of 13 micromol Gd/kg-1 of P792 (n = 10), 100 (n = 10), or 50 micromol Gd/kg-1 of Gd-DOTA (n = 5). Signal-time curves from 6 regions of interest (ROIs), including renal parenchyma and contents, were analyzed. RESULTS: Qualitative analysis depicted a typical pattern of temporal enhancement as previously described with extracellular gadolinium chelates, including early and brief enhancement of the aorta, renal vessels and cortex, quickly followed by enhancement of the medulla and then renal pelvis. However, a decrease in signal intensity was noted in the inner medulla and the renal pelvis approximately 90 seconds after bolus injection, being more marked when using the full dose of Gd-DOTA. Curve analysis showed a similar vascular phase within each parenchymal ROI, confirmed by similar upslopes, which ranged from 0.015 +/- 0.007 to 0.019 +/- 0.005. Following this initial phase, T1-enhancement appeared greater and longer within the medulla and renal pelvis, and subsequently in the whole kidney ROI with P792 (time to maximal enhancement (sec)/ enhancement rate: 85.5 +/- 15.9/3.1 +/- 0.4) as compared with Gd-DOTA full (53.0 +/- 18.9/ 2.7 +/- 0.3) or half dosage (65.2 +/- 20.1/ 2.2 +/- 0.2). The subsequent decrease in signal intensity, characterized by a downslope during the minute following maximal enhancement, was faster with Gd-DOTA (0.006 +/- 0.002) as compared either to P792 or half dosage Gd-DOTA (0.003 +/- 0.001). CONCLUSIONS: Due to its physicochemical and pharmacokinetic properties, P792 allows the use of a reduced dosage of gadolinium, resulting in less T2* effect without compromising T1 enhancement. Thus, P792 appears suitable for renal functional MR imaging.

Animals↗

PubMed2005

Variability in the description of morphologic and contrast enhancement characteristics of breast lesions on magnetic resonance imaging.

RATIONALE AND OBJECTIVE: The objective of this study was to evaluate the interobserver variability in reporting descriptive kinetic and morphologic enhancement features at breast magnetic resonance imaging. MATERIALS AND METHODS: Four observers evaluated 103 lesions, 49 malignant and 54 benign, proven by histopathology. They used standardized terminology with the following characteristics: "early enhancement kinetics" and "late enhancement kinetics" in curves from both reader-determined and preset regions of interest (ROIs), "enhancement pattern," "shape," "margin," "internal enhancement," and a final assessment score. Agreement was calculated using the kappa statistic. Differences in agreement were calculated using Fisher exact test. RESULTS: kappa was 0.27 for both early and late enhancement; preset ROIs improved kappa to 0.47 and 0.67, respectively (odds ratios, 1.7 and 4.5). kappa was 0.45 for pattern, 0.42 for shape, 0.26 for margin, 0.25 for internal enhancement, and 0.28 for final assessment. CONCLUSIONS: There was considerable variability in the use of most generally accepted terms. The preparation of ROIs was a major source of variability in the interpretation of enhancement curves.

Breast Neoplasms↗