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Results for “Enhancer”

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PubMed1994

Dynamic Gd-DOTA-enhanced MR imaging of hepatic metastases from pancreatic neuroendocrine tumors.

The aim of this study was to determine the MR imaging features of hepatic metastases from pancreatic neuroendocrine tumors (HMPNT), and to assess their enhancement characteristics on dynamic gadolinium-chelate-enhanced MR imaging. Twelve consecutive patients with pathologically proven HMPNT underwent spin-echo (SE) and dynamic gradient-recalled echo (GRE) MR imaging before and after intravenous administration of a gadolinium-chelate (gadolinium tetraazacyclododecanetetraacetic acid; Gd-DOTA). MR examinations were performed prospectively and interpreted retrospectively in consensus by two radiologists. Fifty-five HMPNT were identified in matching anatomic sections on the different MR sequences and included in the study. On T1-weighted SE images, 45 HMPNT (82%) were hypointense and 10 HMPNT (18%) were isointense. On T2-weighted SE images 55 HMPNT (100%) were hyperintense. On GRE images obtained 20 s after Gd-DOTA injection, 41 HMPNT (75%) showed slight peripheral enhancement, and 14 HMPNT (25%) showed internal enhancement. Forty-four HMPNT (80%) were heterogeneous. On GRE images obtained 4 min after Gd-DOTA injection, 37 HMPNT (67%) showed peripheral enhancement, and 18 HMPNT (33%) showed a global and almost complete enhancement. Heterogeneity of enhancement was seen in all 55 HMPNT (100%). Although HMPNT exhibit a large spectrum of MR features, early enhancement and heterogeneity on dynamic GRE MR images are suggestive features of HMPNT.

Adult↗

PubMed2003

Regulation of the FGF-4 gene by a complex distal enhancer that functions in part as an enhanceosome.

The exact mechanisms by which enhancers regulate transcription are currently under investigation. For some genes, activation is accomplished by an intricate array of enhancer cis-regulatory elements that direct the assembly of a gene-specific activation complex known as an "enhanceosome". Transcription of the fibroblast growth factor-4 (FGF-4) gene during early development is controlled by a powerful distal enhancer located 3 kb downstream of the transcription start site within the 3' untranslated region of the gene. Previous studies have shown that FGF-4 enhancer function is mediated by at least three critical positive cis-regulatory elements: an HMG, a POU, and a GT-box motif, which bind the transcription factors Sox-2, Oct-3, and Sp1/Sp3, respectively. In this study, we identify a second essential HMG motif within the FGF-4 enhancer that binds the transcription factor Sox-2. Moreover, we demonstrate that spatial alignment of the new HMG motif, relative the other enhancer cis-regulatory elements, is important. Based on findings presented in this report, and work published earlier, we propose that the previously identified core HMG and POU cis-regulatory elements of the FGF-4 enhancer are dependent on one another and function in an enhanceosome-like manner. In contrast, the HMG motif identified in this study is only partially dependent on the other enhancer cis-regulatory elements for its function.

Animals↗

PubMed2004

Evolution of human IgH3'EC duplicated structures: both enhancers HS1,2 are polymorphic with variation of transcription factor's consensus sites.

The enhancer complex regulatory region at the 3' of the immunoglobulin heavy cluster (IgH3'EC) is duplicated in apes along with four constant genes and the region is highly conserved throughout humans. Both human IgH3'ECs consist of three loci high sensitive (HS) to DNAse I with enhancer activity. It is thus possible that the presence of structural divergences between the two IgH3'ECs and of relative polymorphisms correspond to functional regulatory changes. To analyse the polymorphisms of these almost identical regions, it resulted mandatory to identify the presence of divergent sequences, in order to select distinctive primers for specific PCR genomic amplifications. To this aim, we first compared the two entire IgH3'ECs in silicio, utilising the updated GenBank (GB) contigs, then we analysed the two IgH3'ECs by cloning and sequencing amplicons from independent genomes. In silicio analysis showed that several inversions, deletions and short insertions had occurred after the duplication. We analysed in detail, by sequencing specific regions, the polymorphisms occurring in enhancer HS1,2-A (which lies in IgH3'EC-1, 3' to the Calpha-1 gene) and in enhancer HS1,2-B (which lies in IgH3'EC-2, 3' to Calpha-2). Polymorphisms are due to the repetition (occurring one to four times) of a 38-bp sequence present at the 3' of the core of enhancers HS1,2. The structure of both human HS1,2 enhancers has revealed not yet described polymorphic features due to the presence of variable spacer elements separating the 38-bp repetitions and to variable external elements bordering the repetition cluster. We found that one of the external elements gave rise to a divergent allele 3 in the two clusters. The frequency of the different alleles of the two loci varies in the Italian population and allele 3 of both loci are very rare. The analysis of the Callicebus moloch, Gorilla gorilla and Pan troglodytes HS1,2 enhancers showed the transformation from the ancestral structure with the 31- to the 17-bp external element in hominids. The relevance of the polymorphisms in the HS1,2 enhancers is due to the variable number of binding sites for the transcription factors: NF-kappaB, CMYB, BSAP1/2, AP1/4, E47, MyoD and muE5 and thus to the possible influence of these variations on switch, production of Ig and on maturation of B cells.

Animals↗

PubMed2005

Late gadolinium-enhanced magnetic resonance imaging in acute and chronic myocardial infarction. Improved prediction of regional myocardial contraction in the chronic state by measuring thickness of nonenhanced myocardium.

OBJECTIVES: We sought to determine serial changes of enhanced and nonenhanced tissue on late gadolinium-enhanced cardiac magnetic resonance (CMR) imaging in patients with a myocardial infarction (MI) and to assess whether thickness of nonenhanced myocardium can improve the detection of preserved contractile function in the chronic state. BACKGROUND: Previous studies demonstrated that enhancement on late gadolinium-enhanced CMR images indicates myocardial necrosis, and nonenhancement shows the presence of viable myocardium. METHODS: The CMR studies were performed within one week (scan 1) and more than five months (scan 2) after the onset of MI in 18 patients. The area and mean thickness of enhanced tissue and nonenhanced myocardium were measured by using a 30-segment model. Systolic wall thickening on cine CMR at scan 2 was assessed for evaluating regional contractile function. RESULTS: The amount of enhanced tissue significantly decreased from scan 1 to 2 (22.1 +/- 14.0 ml vs. 15.0 +/- 9.3 ml, p < 0.001). The averaged thickness of nonenhanced myocardium in the infarct segments significantly increased from scan 1 to 2 (5.2 +/- 3.0 mm vs. 6.6 +/- 3.2 mm, p < 0.001). Receiver operating characteristic analysis demonstrated that the measurement of thickness of nonenhanced myocardium, compared with measurement of percent transmural enhancement, had better diagnostic accuracy for predicting improved systolic wall thickening form scan 1 to 2 in dysfunctional segments (Az 0.650 vs. 0.594, p < 0.05). CONCLUSIONS: The amounts of enhanced tissue and nonenhanced myocardium significantly altered from the acute to chronic state in MI patients. The diagnostic performance of CMR imaging for detection of preserved contractile function can be significantly improved by measuring thickness of nonenhanced myocardium in MI patients.

Aged↗

PubMed2005

YY1 and GATA-1 interaction modulate the chicken 3'-side alpha-globin enhancer activity.

Studying the chicken alpha-globin domain as a model system of gene regulation, we have previously identified contiguous silencer-enhancer elements located on the 3'-side of the domain. To better characterize the enhancer we performed a systematic functional analysis to define its expression influence range and the ubiquitous and stage-specific transcriptional regulators interacting with this control element. In contrast to previous reports, we found that, in addition to a core element that includes three GATA-1 binding sites, the enhancer incorporates a 120 base-pair DNA fragment where EKLF, NF-E2 and a fourth GATA-1 factor could interact. Functional experiments demonstrate that the enhancer activity over the adult alpha(D) promoter is differentially regulated. We found that the transcriptional factor Ying Yang 1 (YY1) binds to the 120 base-pair DNA fragment and its effect over the enhancer activity is GATA-1-dependent. In addition, we characterize a novel physical interaction between GATA-1 and YY1 that influences the enhancer function. Experiments using a histone deacetylation inhibitor indicate that, in pre-erythroblasts, the enhancer down-regulation could be influenced by a closed chromatin conformation. Our observations show that the originally defined enhancer possesses a more complex composition than previously assumed. We propose that its activity is modulated through differential nuclear factor interactions and chromatin modifications at distinct erythroid stages.

3' Flanking Region↗

PubMed2006

Analysis of Fibroblast growth factor 15 cis-elements reveals two conserved enhancers which are closely related to cardiac outflow tract development.

Fibroblast growth factor 15 (Fgf15) is expressed in the developing mouse central nervous system and pharyngeal arches. Fgf15 mutant mice showed defects of the cardiac outflow tract probably because of aberrant behavior of the cardiac neural crest cells. In this study, we examined cis-elements of the Fgf15 gene by transient transgenic analysis using lacZ as a reporter. We identified two enhancers: one directed lacZ expression in the hindbrain/spinal cord and the other in the posterior midbrain (pmb), rhombomere1 (r1) and pharyngeal epithelia. Interestingly, human genomic regions which are highly homologous to these two mouse enhancers showed almost the same enhancer activities as those of mice in transgenic mouse embryos, indicating that the two enhancers are conserved between humans and mice. We also showed that the mouse and human pmb/r1 enhancer can regulate lacZ expression in chick embryos in almost the same way as in mouse embryos. We found that the lacZ expression domain with this enhancer was expanded by ectopic Fgf8b expression, suggesting that this enhancer is regulated by Fgf8 signaling. Moreover, over-expression of Fgf15 resulted in up-regulation of Fgf8 expression in the isthmus/r1. These findings suggest that a reciprocal positive regulation exists between Fgf15 and Fgf8 in the isthmus/r1. Together with cardiac outflow tract defects in Fgf15 mutants, the conservation of enhancers in the hindbrain/spinal cord and pharyngeal epithelia suggests that human FGF19 (ortholog of Fgf15) is involved in early development and the distribution of cardiac neural crest cells and is one of the candidate genes for congenital heart defects.

Animals↗

PubMed2004

Mef2c is activated directly by Ets transcription factors through an evolutionarily conserved endothelial cell-specific enhancer.

Members of the Myocyte Enhancer Factor 2 (MEF2) family of transcription factors play key roles in the development and differentiation of numerous cell types during mammalian development, including the vascular endothelium. Mef2c is expressed very early in the development of the endothelium, and genetic studies in mice have demonstrated that mef2c is required for vascular development. However, the transcriptional pathways involving MEF2C during endothelial cell development have not been defined. As a first step towards identifying the transcriptional factors upstream of MEF2C in the vascular endothelium, we screened for transcriptional enhancers from the mouse mef2c gene that regulate vascular expression in vivo. In this study, we identified a transcriptional enhancer from the mouse mef2c gene sufficient to direct expression to the vascular endothelium in transgenic embryos. This enhancer is active in endothelial cells within the developing vascular system from very early stages in vasculogenesis, and the enhancer remains robustly active in the vascular endothelium during embryogenesis and in adulthood. This mef2c endothelial cell enhancer contains four perfect consensus Ets transcription factor binding sites that are efficiently bound by Ets-1 protein in vitro and are required for enhancer function in transgenic embryos. Thus, these studies identify mef2c as a direct transcriptional target of Ets factors via an evolutionarily conserved transcriptional enhancer and establish a direct link between these two early regulators of vascular gene expression during endothelial cell development in vivo.

Animals↗

PubMed2005

Multiple N-cadherin enhancers identified by systematic functional screening indicate its Group B1 SOX-dependent regulation in neural and placodal development.

Neural plate and sensory placodes share the expression of N-cadherin and Group B1 Sox genes, represented by Sox2. A 219-kb region of the chicken genome centered by the N-cadherin gene was scanned for neural and placodal enhancers. Random subfragments of 4.5 kb average length were prepared and inserted into tkEGFP reporter vector to construct a library with threefold coverage of the region. Each clone was then transfected into N-cadherin-positive (lens, retina and forebrain) or -negative embryonic cells, or electroporated into early chicken embryos to examine enhancer activity. Enhancers 1-4 active in the CNS/placode derivatives and non-specific Enhancer 5 were identified by transfection, while electroporation of early embryos confirmed enhancers 2-4 as having activity in the early CNS and/or sensory placodes but with unique spatiotemporal specificities. Enhancers 2-4 are dependent on SOX-binding sites, and misexpression of Group B1 Sox genes in the head ectoderm caused ectopic development of placodes expressing N-cadherin, indicating the involvement of Group B1 Sox functions in N-cadherin regulation. Enhancers 1, 2 and 4 correspond to sequence blocks conserved between the chicken and mammalian genomes, but enhancers 3 and 5 are unique to the chicken.

Animals↗

PubMed1995

Contrast-enhanced MR imaging of intrahepatic cholangiocarcinoma.

The unenhanced spin-echo T1-weighted images, contrast-enhanced (dynamic and conventional) T1-weighted images and spin-echo T2-weighted images of 19 patients with histologically proven intrahepatic cholangiocarcinoma were reviewed. The results showed that typical intrahepatic cholangiocarcinoma presented as a large mass of low signal intensity on T1-weighted images. On T2-weighted images tumours generally presented as high signal intensity masses. In five patients the tumours exhibited varying degrees of central hypointensity on T2-weighted images. On contrast-enhanced images, large tumours (diameter larger than 4 cm, n = 14) typically showed peripheral enhancement with delayed or incomplete central filling. This pattern was seen most commonly. Smaller tumours (diam. 2-4 cm, n = 5) typically exhibited homogenous enhancement. On dynamic studies, enhancement of the tumours showed a centripetal pattern. Complete enhancement was observed in the small tumours. Among the larger lesions central sparing of the tumours was seen. It is concluded that contrast-enhanced MR imaging is useful in the diagnosis of intrahepatic cholangiocarcinoma. The characteristic enhancing pattern of intrahepatic cholangiocarcinoma was seen less commonly in smaller tumours. Definite differentiation from other liver masses in this case could be less certain.

Adult↗

PubMed1996

Advantages of an increased dose of MRI contrast agent for enhancing inflammatory synovium.

MRI intravenous contrast enhancement of inflammatory synovium has been studied at two different doses to determine to what extent enhancement is dose dependent. 19 patients with clinically active rheumatoid arthritis involving a knee were scanned twice, one week apart, using 0.1 mmol/kg of gadoteridol (ProHance) on the first occasion and 0.3 mmol/kg on the second. Static pre-and post-contrast images together with dynamic images immediately following injection were obtained on a 1.0T scanner. On subjective assessment, 84% of patients showed improved enhancement. 47% showed more enhancing tissue, a clearer delineation of enhancing tissue or both. Objectively, enhancement was increased significantly at the higher dose, as judged by the percentage increase in mean signal intensity within regions of interest plotted over the suprapatellar pouch (1723% v. 1005% enhancement P < 0.05). In practical terms the better visualization of enhancing tissue achieved with higher doses is likely to reduce margins of error in attempts at quantification from MRI scans, particularly of synovial volume, but emphasizes also the need for care and consistency to be exercised in calculating the exact dose of contrast medium to be administered.

Adult↗

PubMed1997

Evaluation of the role of the 3'alpha heavy chain enhancer [3'alpha E(hs1,2)] in Vh gene somatic hypermutation.

Previous work on the cis-acting elements that control heavy chain variable region (VH) gene somatic hypermutation has indicated the presence of an as yet unidentified element(s) 3' of the intron enhancer that is necessary for high rate mutation. Examination of cis-acting elements involved in kappa light chain V gene hypermutation has demonstrated a requirement for both the intronic and 3' kappa enhancers in this process. To examine whether the 3'alpha heavy chain enhancer [3'alpha E(hs1,2)] is required for somatic hypermutation of VH genes, we generated two types of transgenic mice. One type was generated using a construct containing a VH promoter, a rearranged VDJ, the heavy chain intronic enhancer, and the murine heavy chain 3'alpha E(hs1,2). The transgenes in the second lines were similar to the transgenes in the first with the addition of a second complete matrix attachment region (MAR) 3' of the heavy chain intronic enhancer, and splice acceptor and polyadenylation sites between the two enhancers. Analysis of both transgenes revealed levels of mutation at least 10-fold lower than endogenous VH genes. These data suggest that the 3'alpha E(hs1,2) does not play a role analogous to the 3' kappa enhancer in the regulation of the hypermutation process. Moreover, in one of the transgenes, the presence of the 3'alpha E(hs1,2) resulted in a lack of transcription in vivo, suggesting a negative regulatory role for this enhancer in certain contexts.

Animals↗

PubMed2004

Multidetector helical computed tomography of the liver: comparison of hepatic enhancement using two different contrast media strategies.

RATIONALE AND OBJECTIVES: The purpose of this study was to compare hepatic enhancement characteristics using two different contrast media injection protocols with multidetector helical computed tomography. MATERIALS AND METHODS: Twenty-three patients with known or suspected liver lesions scheduled to undergo biphasic hepatic multidetector helical computed tomography were randomized into one of two groups: (1) 150 mL of iopamidol (300 mgI/mL) at 5 mL/second, or (2) 100 mL of iopamidol (370 mgI/mL) at 4 mL/second. Unenhanced images were acquired initially, followed by both hepatic arterial phase (scan delay, 33 seconds) and portal venous phase (PVP; scan delay, 65 seconds) imaging. Three abdominal radiologists independently graded the images on a scale from 1-5 for enhancement and overall scan quality. Time-attenuation curves were generated from operator-defined region-of-interest measurements of liver parenchyma and aorta. RESULTS: Qualitatively, the three reviewers found no significant difference between the two study groups in terms of overall scan quality (P = .23) or aortic enhancement (hepatic arterial phase, P = .9; PVP, P = .24). However, liver enhancement during the PVP was considered to be less in the Isovue 370 group (P = .04). Quantitatively, during the hepatic arterial phase, there was no statistically significant difference between the two injection protocols comparing either aortic or hepatic parenchymal enhancement (P = .62 and .80, respectively). During the PVP, these differences were statistically significant, with both aortic and hepatic parenchymal enhancement lower in the Isovue 370 group (P < .01 and P = .04, respectively). CONCLUSION: It is important to consider the amount of iodine injected per second and the duration of the injection when setting up protocols to achieve target organ enhancement. 100 mL of iopamidol 370 at 4 mL/second can be used to obtain images of the liver with good diagnostic quality compared to more conventional protocols using 150 mL of iopamidol 300 at 5 mL/second. However, the degree of liver parenchymal enhancement during the PVP using the latter injection scheme is lower, which in turn could potentially reduce hepatic lesion conspicuity.

Adult↗

PubMed1996

Quantitative analysis of signal intensities and contrast after fat suppression in contrast-enhanced magnetic resonance imaging of the spine.

RATIONALE AND OBJECTIVES: We studied the effect of fat suppression on signal intensity and contrast on contrast-enhanced magnetic resonance (MR) images of the spine. METHODS: Contrast-enhanced T1-weighted MR images were obtained at identical levels with and without fat suppression. Signal intensity and contrast were measured in regions of interest in fat, muscle, spinal bone marrow, and enhancing lesions. The differences in the mean values of these signal intensities and the mean values of contrast between enhanced tissues and bone marrow, fat, and muscle were subjected to statistical validation. RESULTS: Mean signal intensity of the extraspinal fat and bone marrow was lower after fat suppression (70% and 46% reduction, p < .001 and p < .05, respectively), whereas the signal intensity of muscle showed no significant change (p < .9). Enhancing spinal lesions showed a difference in mean signal intensity after fat suppression (22% increase, p < .2). Contrast between enhanced lesions and bone marrow and fat was higher after fat suppression (78% increase, p < .01 for bone marrow; 8% increase, p < .001 for fat). CONCLUSION: In contrast-enhanced MR examinations of the spine, the use of fat suppression may increase the signal intensity of the enhancing lesion by expanding the dynamic gray scale of the image and increases the contrast between the lesion and adjacent bone marrow and suppressed fat.

Adipose Tissue↗

PubMed2000

A four-nucleotide translation enhancer in the 3'-terminal consensus sequence of the nonpolyadenylated mRNAs of rotavirus.

The 5' cap and poly(A) tail of eukaryotic mRNAs work synergistically to enhance translation through a process that requires interaction of the cap-associated eukaryotic initiation factor, eIF-4G, and the poly(A)-binding protein, PABP. Because the mRNAs of rotavirus, and other members of the Reoviridae, contain caps but lack poly(A) tails, their translation may be enhanced through a unique mechanism. To identify translation-enhancement elements in the viral mRNAs that stimulate translation in vivo, chimeric RNAs were prepared that contained an open reading frame for luciferase and the 5' and 3' untranslated regions (UTRs) of a rotavirus mRNA or of a nonviral mRNA. Transfection of the chimeric RNAs into rotavirus-infected cells showed that the viral 3' UTR contained a translation-enhancement element that promoted gene expression. The element did not enhance gene expression in uninfected cells and did not affect the stability of the RNAs. Mutagenesis showed that the conserved sequence GACC located at the 3' end of rotavirus mRNAs operated as an enhancement element. The 3'-GACC element stimulated protein expression independently of the sequence of the 5' UTR, although efficient expression required the RNA to contain a cap. The results indicate that the expression of viral proteins in rotavirus-infected cells is specifically up-regulated by the activity of a novel 4-nt 3' translation enhancer (TE) common to the 11 nonpolyadenylated mRNAs of the virus. The 4-nt sequence of the rotavirus 3' TE represents by far the shortest of any of the sequence enhancers known to stimulate translation.

3' Untranslated Regions↗

PubMed2002

Triple-dose contrast/magnetization transfer suppressed imaging of 'non-enhancing' brain gliomas.

PURPOSE: Triple-dose (TD) gadolinium contrast administration and magnetization transfer suppression (MTS) in brain magnetic resonance imaging (MRI) have proven to be useful for demonstrating additional enhancing lesions in some diseases. The purpose of this study was to determine if there is a subset of brain tumors that demonstrate contrast enhancement with TD and MTS that do not enhance with standard imaging and standard contrast dose. MATERIALS AND METHODS: Fifteen patients with either newly diagnosed primary brain tumor or brain tumor that had been followed for more than 2 years were enrolled. T1-weighted MTS images without IV contrast, with 0.1 mmol/kg without MTS (single-dose (SD) images), and with additional 0.2 mmol/kg gadolinium and MTS ('TD/MTS') were obtained. RESULTS: None of the patients had enhancement on SD images. Six patients had areas of enhancement on TD/MTS images ('exact' chi-squared p = 0.017). CONCLUSION: A statistically significant increased rate of contrast enhancement was found on TD/MTS images in patients whose tumors did not enhance at single dose without MTS. It is possible that small areas of enhancement seen only with TD/MTS might represent areas of higher-grade tumor.

Brain Neoplasms↗

PubMed2004

Bi-directional duplex promoters with duplicated enhancers significantly increase transgene expression in grape and tobacco.

Novel bi-directional duplex promoters (BDDP) were constructed by placing two identical core promoters divergently on both upstream and downstream sides of their duplicated enhancer elements. Estimates of promoter function were obtained by creating versions of CaMV 35S and CsVMV BDDPs that contained reporter marker genes encoding beta-glucuronidase (GUS) and enhanced green fluorescent protein (EGFP) interchangeably linked either to the upstream or downstream core promoters. GUS was used for quantitative analysis of promoter function, whereas, EGFP allowed visual qualitative evaluation. In addition, the GUS and EGFP genes placed in downstream positions were modified by translational fusion with neomycin phosphotransferase (NPTII) to allow simultaneous monitoring of promoter activity and selection of stable transformants. These versions of BDDP were compared with each other and with equivalent unidirectional constructs by evaluating their expression in grape and tobacco. For 35S promoter constructs tested in grape somatic embryos (SE), BDDP exhibited transient GUS expression 206- and 300-fold greater in downstream and upstream configurations, respectively, compared to a unidirectional 35S core promoter. Compared with a unidirectional double enhanced 35S promoter, BDDPs exhibited 0.5- and 3-fold increased GUS expression from downstream and upstream core promoters, respectively. The same differences in expression levels determined quantitatively with GUS were distinguished qualitatively with EGFP. Constructs using CsVMV core promoters yielded results relative to those obtained with 35S promoter. For example, the upstream BDDP CsVMV core promoter provided a 200-fold increase in GUS expression compared to a unidirectional core promoter. However, CsVMV promoter was found to have higher promoter activity than 35S promoter in both BDDP and unidirectional constructs. Incorporation of an additional duplicated enhancer element to BDDPs resulted in increased expression. For example, a 35S BDDP with two divergently arranged duplicated enhancer elements resulted in over a 6-fold increase in GUS expression in stably transformed tobacco plants compared to a BDDP with one duplicated enhancer element. Data demonstrate that BDDP composed of divergently-arranged core promoters separated by duplicated enhancers, all derived from a single promoter sequence, can be used to significantly enhance transgene expression and to direct synchronized expression of multiple transgenes.

Amino Acid Oxidoreductases↗

PubMed1990

A second B cell-specific enhancer 3' of the immunoglobulin heavy-chain locus.

The expression of immunoglobulin heavy-chain (IgH) genes is generally thought to be regulated by the combination of the VH promoter with the enhancer element which is located in the JH-CH intron. This is probably an oversimplification: there are cell lines that transcribe IgH genes despite the deletion of the intron-enhancer. These findings could imply that other enhancer element(s) exist in the IgH locus. Here we show that a strong B-cell-specific enhancer is indeed located at the 3'-end of the rat IgH locus, 25 kilobases downstream of C alpha. This enhancer should be retained downstream of all rearranged IgH genes, regardless of the VH or CH segment used. Taken together with analogous findings for the mouse kappa locus, the results prompt a re-evaluation of the mechanism of regulation of immunoglobulin gene transcription. Furthermore, unlike the intron-enhancer, the IgH 3' enhancer would become linked to a c-myc that rearranges into an IgH switch region. The IgH 3' enhancer could therefore play a part in the activation of the translocated c-myc genes in rat immunocytomas, mouse plasmacytomas and Burkitt lymphomas.

Animals↗

PubMed2026

Nuclear exosome targeting complexes modulate cohesin binding and enhancer-promoter interactions in 3D.

Three-dimensional long-range contacts between enhancers and promoters are thought to be largely determined by loop extrusion driven by the cohesin complex and insulator factors. However, recent evidence also suggests a role for noncoding RNAs, such as enhancer-associated RNAs and promoter upstream transcripts, in shaping enhancer-promoter connectivity. While the nuclear RNA exosome, together with targeting complexes, poly(A) tail exosome targeting connection and nuclear exosome targeting complex, controls the decay of noncoding RNAs, it remains unclear whether these complexes regulate three-dimensional chromatin contacts. Chromatin recruitment maps of the nuclear exosome targeting complex subunit ZCCHC8, the poly(A) tail exosome targeting connection subunit ZFC3H1, and the RNA helicase MTR4 in human cells reveal that these factors associate with sites of enhancer-promoter interactions. Depletion of these factors leads to the accumulation of ncRNAs, notably enhancer-associated RNAs and promoter upstream transcripts, and increases cohesin occupancy at these sites. Chromatin conformation capture analysis reveals that MTR4 modulates long-range enhancer-promoter contacts. Upon loss of MTR4, enhancer-promoter contacts increase while intraloop contacts decrease, suggesting that MTR4 facilitates loop extrusion. These data highlight a key interplay between cohesin-mediated enhancer-promoter interactions and the regulation of noncoding RNAs by nuclear RNA exosome targeting complexes that is consistent with a role for RNA in genome folding.

Cohesins↗