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PubMed2004

Local induction of the alc gene switch in transgenic tobacco plants by acetaldehyde.

The alc promoter system, derived from the filamentous fungi Aspergillus nidulans, allows chemically regulated gene expression in plants and thereby the study of gene function as well as metabolic and developmental processes. In addition to ethanol, this system can be activated by acetaldehyde, described as the physiological inducer in A. nidulans. Here, we show that in contrast to ethanol, acetaldehyde allows tissue-specific activation of the alc promoter in transgenic tobacco plants. Soil drenching with aqueous acetaldehyde solutions at a concentration of 0.05% (v/v) resulted in the rapid and temporary induction of the alc gene expression system exclusively in roots. In addition, the split root system allows activation to be restricted to the treated part of the root. The temporary activation of the alc system by soil drenching with acetaldehyde could be prolonged over several weeks by subsequent applications at intervals of 7 d. This effect was demonstrated for the root-specific induction of a yeast-derived apoplast-located invertase under the control of the alcohol-inducible promoter system. In leaves, which exhibit a lower responsiveness to acetaldehyde than roots, the alc system was induced in the directly treated tissue only. Thus, acetaldehyde can be used as a local inducer of the alc gene expression system in tobacco plants.

Acetaldehyde↗
PubMed2006

Regulation of antisense RNA expression during cardiac MHC gene switching in response to pressure overload.

Hypertension has been shown to cause cardiac hypertrophy and a shift in myosin heavy chain (MHC) gene expression from the faster alpha- to slower beta-MHC isoform. The expression of the beta- and alpha-MHC pre-mRNAs, mRNAs, as well as the newly discovered antisense beta-RNA were analyzed in three regions of the normal control (NC) and 12-day pressure-overloaded (AbCon) hearts: the left ventricle apex, left ventricle base, and the septum. The RNA analyses in the AbCon heart targeted both the 5' and the 3' ends of each RNA molecule. beta-MHC mRNA expression significantly increased relative to control in all three regions, regardless of the target site (5' or 3' end). In contrast, beta-MHC pre-mRNA expression in the AbCon heart depended on the site of the measurement (5' vs. 3' end). For example, whereas the pre-mRNA did not change when targeted at the 3' end (last intron), it increased significantly in the AbCon heart when measurement targeted the 5' end (2nd intron) of the 25-kb molecule. Analyses of the antisense beta-RNA revealed that its expression in the AbCon heart was significantly decreased relative to control regardless of its measurement site. A negative correlation was observed between the beta-mRNA expression and the antisense beta-RNA (P < 0.05), suggesting an inhibitory role of antisense RNA on the sense beta-MHC gene expression. In contrast, a positive correlation was observed between the antisense beta-RNA and the alpha-MHC pre-mRNA (P < 0.05). This latter observation along with the alpha-MHC gene position relative to that of the beta-antisense suggest that the alpha-MHC sense and beta-antisense transcription are coregulated likely via common intergenic regulatory sequences. Our results suggest that the increased beta-MHC expression in the AbCon heart not only is the result of increased beta-MHC transcription but also involves an antisense beta-RNA regulation scheme. Although the exact mechanism concerning antisense regulation is not clear, it could involve modulation of both transcriptional activity of the beta-MHC gene and posttranscriptional processing.

Animals↗
PubMed1981

Gene switching in myogenesis: differential expression of the chicken actin multigene family.

We described the construction of an alpha-actin complementary deoxyribonucleic acid (cDNA) clone, pAC269 [Schwartz, R. J., Haron, J. A., Rothblum, K. N., & Dugaiczyk, A. (1980) Biochemistry 19, 5883], that was used as a hybridization probe in the current investigation to examine the induction of actin messenger ribonucleic acid (mRNA) during myogenesis. A Tm difference of 10-13 degrees C between skeletal muscle alpha-actin and nonmuscle beta- and gamma-actin mRNAs and pAC269 allowed us to establish the highly stringent hybridization conditions necessary to measure separately the content of alpha-actin mRNA and beta- and gamma-actin mRNA during muscle development in culture. We observed low levels of alpha-actin mRNA (approximately 130 molecules/cell) in replicating prefusion myoblasts. The vast majority of actin mRNA (2000 molecules/cell) present at this stage was accounted for by beta- and gamma-actin mRNA. Beginning at myoblast fusion, alpha-actin mRNA accumulated and within 30 h reached a level 270-fold greater than that observed in the undifferentiated state. At 95 h in culture when myotube formation was completed, alpha-actin content was at its peak (36 000 molecules/nucleus). Conversely, beta- and gamma-actin mRNA content began to decline at the beginning of fusion, and by the end of myotube formation beta- and gamma-actin mRNAs were undetectable by our techniques. A rapid depression of alpha-actin mRNA levels was observed after 95 h in the absence of cell death. At 6 days after the initiation of myotube formation, the content of alpha-actin mRNA was reduced by 80% in comparison of peak values and remained at that level. The switching of actin mRNA species was inhibited in myoblasts treated with bdU. The accumulation of alpha-actin mRNA and the disappearance of beta- and gamma-actin mRNA were observed following the reversal of the bdU block and coincident with the onset of myoblast fusion. We found that the expression of actin genes within the actin multigene family is switched in myogenesis through a strict developmental pattern.

Actins↗
PubMed1988

Developmental regulation of beta-globin gene switching.

A chicken erythroid cell-specific enhancer is located in the intergenic region between the adult beta- and embryonic epsilon-globin genes. In this paper we show that the beta-globin enhancer stimulates transcription of both genes. epsilon-Globin is, however, inappropriately regulated since it is expressed in both embryonic and adult red blood cells. Appropriate stage-specific regulation is observed for both genes when they are present on one plasmid. By analysis of deletion and substitution mutants, we conclude that beta-globin tissue- and developmental stage-specific regulation is mediated by interaction of the beta-globin enhancer with a positive regulatory element within the adult beta-globin promoter, the developmental stage selector element (SSE).

Animals↗
PubMed1988

The Leeuwenhoek lecture, 1987. Towards an understanding of gene switching in Streptomyces, the basis of sporulation and antibiotic production.

Streptomycetes are soil bacteria that differ from the genetically well-known Escherichia coli in two striking characteristics. (1) Instead of consisting of an alternation of growth and fission of morphologically simple, undifferentiated rods, the streptomycete life cycle involves the formation of a system of elongated, branching hyphae which, after a period of vegetative growth, respond to specific signals by producing specialized spore-bearing structures. (2) The streptomycetes produce an unrivalled range of chemically diverse 'secondary metabolites', which we recognize as antibiotics, herbicides and pharmacologically active molecules, and which presumably play an important role in the streptomycete life cycle in nature. This 'physiological' differentiation is often temporally associated with the morphological differentiation of sporulation and there are common elements in the regulation of the two sets of processes. In the model system provided by Streptomyces coelicolor A3(2), the isolation of several whole clusters of linked antibiotic biosynthetic pathway genes, and some key regulatory genes involved in sporulation, has made it possible to study the basis for the switching on and off of particular sets of genes during morphological and 'physiological' differentiation. Genetic analysis clearly reveals a regulatory cascade operating at several levels in a 'physiological' branch of the differentiation control system. At the lowest level, within individual clusters of antibiotic biosynthesis genes are genes with a role as activators of the structural genes for the pathway enzymes, and also resistance genes. It is attractive to speculate that the latter play a dual role: protecting the organism from self-destruction by its own potentially lethal product, and forming an essential component of a regulatory circuit that activates the biosynthetic genes, thus ensuring that resistance is established before any antibiotic is made. A next higher level of regulation is revealed by the isolation of mutations in a gene (afsB) required for expression (probably at the level of transcription) of all five known secondary metabolic pathways in the organism. At a higher level still, the bldA gene, whose product seems to be a tRNA essential to translate the rare (in high [G + C] Streptomyces DNA) TTA leucine codon, controls or influences the whole gamut of morphological and 'physiological' differentiation, because bldA mutants fail to produce either secondary metabolites or aerial mycelium and spores, while growing normally in the vegetative phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Bacterial Agents↗
PubMed2005

Gal80 dimerization and the yeast GAL gene switch.

The Saccharomyces cerevisiae Gal80 protein has two binding partners: Gal4 and Gal3. In the absence of galactose, Gal80 binds to and inhibits the transcriptional activation domain (AD) of the GAL gene activator, Gal4, preventing GAL gene expression. Galactose triggers an association between Gal3 and Gal80, relieving Gal80 inhibition of Gal4. We selected for GAL80 mutants with impaired capacity of Gal80 to bind to Gal3 or Gal4AD. Most Gal80 variants selected for impaired binding to Gal4AD retained their capacity to bind to Gal3 and to self-associate, whereas most of those selected for impaired binding to Gal3 lost their ability to bind to Gal4AD and self-associate. Thus, some Gal80 amino acids are determinants for both the Gal80-Gal3 association and the Gal80 self-association, and Gal80 self-association may be required for binding to Gal4AD. We propose that the binding of Gal3 to the Gal80 monomer competes with Gal80 self-association, reducing the amount of the Gal80 dimer available for inhibition of Gal4.

DNA Primers↗
PubMed2004

Hypoxia-induced decrease of UCP3 gene expression in rat heart parallels metabolic gene switching but fails to affect mitochondrial respiratory coupling.

Mitochondrial uncoupling proteins 2 and 3 (UCP2 and UCP3) are postulated to contribute to antioxidant defense, nutrient partitioning, and energy efficiency in the heart. To distinguish isotype function in response to metabolic stress we measured cardiac mitochondrial function and cardiac UCP gene expression following chronic hypobaric hypoxia. Isolated mitochondrial O(2) consumption and ATP synthesis rate were reduced but respiratory coupling was unchanged compared to normoxic groups. Concurrently, left ventricular UCP3 mRNA levels were significantly decreased with hypoxia (p<0.05) while UCP2 levels remained unchanged versus controls. Diminished UCP3 expression was associated with coordinate regulation of counter-regulatory metabolic genes. From these data, we propose a role for UCP3 in the regulation of fatty acid oxidation in the heart as opposed to uncoupling of mitochondria. Moreover, the divergent hypoxia-induced regulation of UCP2 and UCP3 supports distinct mitochondrial regulatory functions of these inner mitochondrial membrane proteins in the heart in response to metabolic stress.

Animals↗
PubMed1993

Serum factors can modulate the developmental clock of gamma- to beta-globin gene switching in somatic cell hybrids.

The fusion of human fetal erythroid (HFE) cells with mouse erythroleukemia (MEL) cells produces stable synkaryons (HFE x MEL) which can be monitored for extended periods of time in culture. Initially these hybrids express a human fetal globin program (gamma >> beta), but after weeks or months in culture, they switch to an adult pattern of globin expression (beta >> gamma). The rate at which hybrids switch to the adult phenotype is roughly dependent on the gestational age of the fetal erythroid cells used in the fusion, suggesting that the rate of switching in vitro may be determined by a developmental clock type of mechanism, possibly involving the cumulative number of divisions experienced by the human fetal cells. To investigate whether the number or rate of cell divisions postfusion can influence the rate of switching, we monitored the rate of switching in hybrids from independent fusions under growth-promoting (serum-replete) and growth-suppressing (serum-deprived) conditions. We found that hybrids grown under serum-deprived or serumless conditions switched more rapidly to adult globin expression than did their counterparts in serum-replete conditions. Neither the number of cumulative cell divisions nor time in culture per se predicted the rate of switching in vitro. Our data suggest that factors present in serum either retard switching of hybrids by their presence or promote switching by their absence, indicating that globin switching in vitro can be modulated by the environment; however, once switching in HFE x MEL hybrids is complete, serum factors cannot reverse this process.

Animals↗
PubMed2000

Expression of thaumatin-like permatin PR-5 genes switches from the ovary wall to the aleurone in developing barley and oat seeds.

Permatins are antifungal thaumatin-like proteins (TLPs) of the PR-5 family of pathogenesis-related proteins. They occur in many cereals, but little is known of their expression and roles. Permatin cDNA clones were produced and used to study expression in developing barley and oat seeds. Actin and CDC48 mRNAs declined rapidly following inoculation of barley spikes with Fusarium graminearum. Despite this, permatin mRNA levels remained constant or increased slightly. Studies of permatin gene expression in healthy plants revealed that developing barley and oat seeds accumulate permatin mRNA in an unusual bimodal pattern. Permatin mRNA and protein are highly abundant around the time of pollination and then decrease rapidly to near-zero. A second peak occurs in the doughy stage of development. Antibody and DNA probe hybridization studies showed that expression initially occurs in the ovary wall and then switches to the aleurone and ventral furrow of developing seeds, reaching a peak in the doughy stage. Small amounts of permatin mRNAs also occur in certain vegetative tissues. The barley and oat permatin sequences provided sufficient comparisons between cereal TLPs to suggest that deletions or additions in specific elements could have led to the divergence of leaf- and seed-specific TLPs.

Journal Article↗
PubMed2000

Beta-globin gene switching and DNase I sensitivity of the endogenous beta-globin locus in mice do not require the locus control region.

We have generated mice with a targeted deletion of the beta-globin locus control region (LCR). Mice homozygous for the deletion die early in embryogenesis but can be rescued with a YAC containing the human beta-globin locus. After germline passage, deletion of the LCR leads to a severe reduction in expression of all mouse beta-like globin genes, but no alteration in the developmental specificity of expression. Furthermore, a DNase I-sensitive "open" chromatin conformation of the locus is established and maintained. Thus, the dominant role of the LCR in the native locus is to confer high-level transcription, and elements elsewhere in the locus are sufficient to establish and maintain an open conformation and to confer developmentally regulated globin gene expression.

Animals↗
PubMed2004

The Ews/Fli-1 fusion gene switches the differentiation program of neuroblastomas to Ewing sarcoma/peripheral primitive neuroectodermal tumors.

Neuroblastoma (NB) and the Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumor (PNET) family are pediatric cancers derived from neural crest cells. Although NBs display features of the sympathetic nervous system, ES/PNETs express markers consistent with parasympathetic differentiation. To examine the control of these differentiation markers, we generated NB x ES/PNET somatic cell hybrids. NB-specific markers were suppressed in the hybrids, whereas ES/PNET-specific markers were unaffected. These results suggested that the Ews/Fli-1 fusion gene, resulting from a translocation unique to ES/PNETs, might account for the loss of NB-specific markers. To test this hypothesis, we generated two different NB cell lines that stably expressed the Ews/Fli-1 gene. We observed that heterologous expression of the Ews/Fli-1 protein led to the suppression of NB-specific markers and de novo expression of ES/PNET markers. To determine the extent of changes in differentiation, we used the Affymetrix GeneChip Array system to observe global transcriptional changes of genes. This analysis revealed that the gene expression pattern of the Ews/Fli-1-expressing NB cells resembled that observed in pooled ES/PNET cell lines and differed significantly from the NB parental cells. Therefore, we propose that Ews/Fli-1 contributes to the etiology of ES/PNET by subverting the differentiation program of its neural crest precursor cell to a less differentiated and more proliferative state.

Adaptor Proteins, Signal Transducing↗