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Results for “Enhancer Elements, Genetic”

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PubMed2000

Genetic studies of mei-P26 reveal a link between the processes that control germ cell proliferation in both sexes and those that control meiotic exchange in Drosophila.

We present the cloning and characterization of mei-P26, a novel P-element-induced exchange-defective female meiotic mutant in Drosophila melanogaster. Meiotic exchange in females homozygous for mei-P26(1) is reduced in a polar fashion, such that distal chromosomal regions are the most severely affected. Additional alleles generated by duplication of the P element reveal that mei-P26 is also necessary for germline differentiation in both females and males. To further assess the role of mei-P26 in germline differentiation, we tested double mutant combinations of mei-P26 and bag-of-marbles (bam), a gene necessary for the control of germline differentiation and proliferation in both sexes. A null mutation at the bam locus was found to act as a dominant enhancer of mei-P26 in both males and females. Interestingly, meiotic exchange in mei-P26(1); bam(Delta)(86)/+ females is also severely decreased in comparison to mei-P26(1) homozygotes, indicating that bam affects the meiotic phenotype as well. These data suggest that the pathways controlling germline differentiation and meiotic exchange are related and that factors involved in the mitotic divisions of the germline may regulate meiotic recombination.

Alleles↗

PubMed1997

The Pit-1 gene is regulated by distinct early and late pituitary-specific enhancers.

The differentiation of three anterior pituitary cell types is regulated by the tissue-specific POU domain factor Pit-1, which is initially expressed on Embryonic Day 13.5-14 in mice. The Pit-1 gene remains continuously, highly expressed in the somatotrope, thyrotrope, and lactotrope cells of the adult. Using the Pit-1-defective Snell dwarf as a genetic background, we demonstrate that the Pit-1 gene utilizes distinct enhancers for initial gene activation and for subsequent autoregulation (required for maintenance of expression) and that Pit-1-dependent activation of the distal enhancer can be mediated in the absence of the early enhancer. These two distinct enhancers provide the basis for temporally specific regulation by discrete pituitary-specific factors, events likely to be prototypic for regulation of other classes of genes encoding transcription factors controlling terminal differentiation.

Animals↗

PubMed2003

ESEfinder: A web resource to identify exonic splicing enhancers.

Point mutations frequently cause genetic diseases by disrupting the correct pattern of pre-mRNA splicing. The effect of a point mutation within a coding sequence is traditionally attributed to the deduced change in the corresponding amino acid. However, some point mutations can have much more severe effects on the structure of the encoded protein, for example when they inactivate an exonic splicing enhancer (ESE), thereby resulting in exon skipping. ESEs also appear to be especially important in exons that normally undergo alternative splicing. Different classes of ESE consensus motifs have been described, but they are not always easily identified. ESEfinder (http://exon.cshl.edu/ESE/) is a web-based resource that facilitates rapid analysis of exon sequences to identify putative ESEs responsive to the human SR proteins SF2/ASF, SC35, SRp40 and SRp55, and to predict whether exonic mutations disrupt such elements.

Base Sequence↗

PubMed2000

A site specific increase in recombination in Drosophila ananassae.

The e65 pi; bri ru stock of Drosophila ananassae produced an extremely high rate of recombination in males when made heterozygous with any one of the wild type stocks. We analyzed and characterized the genetic factors which caused this phenomenon. We show that the second chromosome of the e65 pi; bri ru stock carries an enhancer of male recombination. The enhancer, En(2)-ep, is located between Om(2C) and Arc. The enhancement of meiotic recombination both in males and females was also observed at the specific region between Om(2C) and Arc on 2L. The magnitude of increased recombination was 30-40 fold in males and 13-30 fold in females. The relation between the hotspot of recombination in both sexes and the enhancer of male recombination is discussed.

Animals↗

PubMed1992

Alternate translation initiation on hepatitis B virus X mRNA produces multiple polypeptides that differentially transactivate class II and III promoters.

The hepatitis B virus X gene encodes a transcription activator which stimulates the synthesis of RNAs from a variety of class II and III promoter elements. In this report, we present a mutational analysis which genetically demonstrates that the X gene actually encodes two, and possibly three, related polypeptides from a single mRNA using alternate translation initiation from any of three in-frame AUG codons. Genetic analysis shows that translation initiates at the 5' proximal AUG of X mRNA and produces a full-length 17-kDa X protein but in addition also likely initiates at either of two conserved, in-frame AUG codons, producing two amino-terminally truncated X proteins presumably of 8 and 6.6 kDa. Expression of mRNAs capable of encoding only one of each X protein all individually transactivate class III (RNA polymerase III)-transcribed promoters. However, class II (RNA polymerase II)-transcribed promoters displayed various requirements for the different X proteins. Expression of two X proteins, the 17- and 6.6-kDa species, was required to activate transcription of the simian virus 40 enhancer/early promoter. In contrast, activation of an NF-kappa B-dependent promoter was carried out only by mRNAs encoding the full-length 17-kDa X protein. These results indicate that the X gene encodes several related proteins that possess different transcriptional regulatory activities.

Codon↗

PubMed1992

Ultrabithorax is a regulator of beta 3 tubulin expression in the Drosophila visceral mesoderm.

beta 3 tubulin expression accompanies the specification and differentiation of the Drosophila mesoderm. The genetic programs involved in these processes are largely unknown. Our previous studies on the regulation of the beta 3 tubulin gene have shown that upstream sequences guide the expression in the somatic musculature, while regulatory elements in the first intron are necessary for expression in the visceral musculature. To further analyse this mode of regulation, which reflects an early embryonic specification program, we undertook a more detailed analysis of the regulatory capabilities of the intron. The results reveal not only a certain degree of redundancy in the cis-acting elements, which act at different developmental stages in the same mesodermal derivatives, but they also demonstrate in the visceral mesoderm, which forms a continuous epithelium along the body axis of the embryo, an early action of regulators guiding gene expression along the anterior-posterior axis of the embryo: an enhancer element in the intron leads to expression in a subdomain restricted along the anterior-posterior axis. This pattern is altered in mutants in the homeotic gene Ultrabithorax (Ubx), whereas ectopic Ubx expression leads to activity of the enhancer in the entire visceral mesoderm. So this element is likely to be a target of homeotic genes, which would define the beta 3 tubulin gene as a realisator gene under the control of selector genes.

Animals↗

PubMed1991

Functional analysis of cis-elements, auxin response and early developmental profiles of the mannopine synthase bidirectional promoter.

The dual MAS1'-2' promoter regulating two divergently transcribed mannopine synthase genes has been widely employed in plant expression vectors. As part of an effort towards its rational design as a genetic engineering tool, we have undertaken a functional analysis of the promoter by deletion mutagenesis and by the use of hybrid promoter constructs. Our results indicate that the central region of the intergenic promoter is composed of at least four domains. Three of these contain complementary sequences, which can potentially hybridize to form alternative palindromic structures. These three domains can function cooperatively, and in an orientation-independent manner, in imparting a sevenfold higher expression level at the 2' end relative to the corresponding 1'. The remaining domain is characterized by tracts of repeated A/T-rich elements, and appears to confer the weak activity at the MAS1' promoter end. However, even though this A/T-rich DNA segment is functional, our deletion analysis provided strong evidence that it is completely dispensable for wild-type promoter activity. In addition, the relative distances between these enhancer domains and the 1'-2' TATA-proximal regions can have a pronounced influence on the level of expression in both directions. In young tobacco seedlings, the two promoter ends are expressed in similar, if not identical, tissues in the aerial parts of the plants, but major differences can be observed in roots. Transient expression assays using hybrid promoter constructs showed that cis-elements that can respond to auxin induction signals are redundant in nature, in that they are dispersed throughout the promoter and showed no obvious consensus sequence.

2,4-Dichlorophenoxyacetic Acid↗

PubMed1991

Stable growth of simian virus 40 recombinants containing multimerized enhancers.

Multiple copies of each of three genetically defined simian virus 40 protoenhancers, A, B, and C, were able to substitute for the wild-type simian virus 40 enhancer. Although the recombinant viruses grew poorly, they could be propagated without the accumulation of enhancer rearrangements that might improve viability. Mutations that inactivate the multimerized B and C protoenhancers abolished virus growth, but, unexpectedly, a mutation that inactivates the octamer-enhanson within the B protoenhancer increased virus viability. This positive effect may reflect loss of repression of the B protoenhancer by the ubiquitous octamer-motif-binding protein Oct-1.

Animals↗

PubMed2005

Genetic mapping of putative Chrna7 and Luzp2 neuronal transcriptional enhancers due to impact of a transgene-insertion and 6.8 Mb deletion in a mouse model of Prader-Willi and Angelman syndromes.

BACKGROUND: Prader-Willi and Angelman syndrome (PWS and AS) patients typically have an approximately 5 Mb deletion of human chromosome 15q11-q13, of opposite parental origin. A mouse model of PWS and AS has a transgenic insertion-deletion (TgPWS/TgAS) of chromosome 7B/C subsequent to paternal or maternal inheritance, respectively. In this study, we define the deletion endpoints and examine the impact on expression of flanking genes. RESULTS: Using molecular and cytological methods we demonstrate that 13 imprinted and 11 non-imprinted genes are included in the TgPWS/TgAS deletion. Normal expression levels were found in TgPWS brain for genes extending 9.1- or 5.6-Mb centromeric or telomeric of the deletion, respectively. Our molecular cytological studies map the proximal deletion breakpoint between the Luzp2 and Siglec-H loci, and we show that overall mRNA levels of Luzp2 in TgPWS and TgAS brain are significantly reduced by 17%. Intriguingly, 5' Chrna7 shows 1.7-fold decreased levels in TgPWS and TgAS brain whereas there is a > or =15-fold increase in expression in neonatal liver and spleen of these mouse models. By isolating a Chrna7-Tg fusion transcript from TgAS mice, we mapped the telomeric deletion breakpoint in Chrna7 intron 4. CONCLUSION: Based on the extent of the deletion, TgPWS/TgAS mice are models for PWS/AS class I deletions. Other than for the first gene promoters immediately outside the deletion, since genes extending 5.6-9.1 Mb away from each end of the deletion show normal expression levels in TgPWS brain, this indicates that the transgene array does not induce silencing and there are no additional linked rearrangements. Using gene expression, non-coding conserved sequence (NCCS) and synteny data, we have genetically mapped a putative Luzp2 neuronal enhancer responsible for approximately 33% of allelic transcriptional activity. The Chrna7 results are explained by hypothesizing loss of an essential neuronal transcriptional enhancer required for approximately 80% of allelic Chrna7 promoter activity, while the Chrna7 promoter is upregulated in B lymphocytes by the transgene immunoglobulin enhancer. The mapping of a putative Chrna7 neuronal enhancer inside the deletion has significant implications for understanding the transcriptional regulation of this schizophrenia-susceptibility candidate gene.

Alleles↗

PubMed2003

From transcriptional regulation to aggressive behavior.

Gene expression in higher organisms, is, to a large degree, controlled at the level of transcription, where DNA-binding proteins (transcription factors) play an influential role in gene regulation. This is achieved through various mechanisms, including those that involve silencer and enhancer regions. Variation in those regulatory regions, as well as in the genes encoding the transcription factors, has been shown to generate functional effects at the molecular, cellular, and neurobehavioral levels. The aim of the present paper is two-fold. First, for the sake of clarity and to reintroduce the terminology to Behavior Genetics readers, we review the concepts of gene structure, gene expression, and gene regulation. Second, using distinct bioinformatic tools, we set out to identify transcription factors that could be involved in the transcriptional regulation of genes known to be associated with aggressive behavior in mice. The results of this in silico study reveal common putative transcription factor binding sites among the set of genes investigated (especially for SRY), suggesting similar molecular transcriptional mechanisms.

Aggression↗

PubMed2003

Methylation at CpG islands in intron 1 of EGR2 confers enhancer-like activity.

We previously demonstrated several lines of evidence indicating that early growth response 2 (EGR2) functions as a tumor suppressor, partly on the basis that its expression was often decreased in human tumors and cancer cell lines. Here we report a possible molecular mechanism to account for down-regulation of EGR2 in tumor cells. Although no genetic mutations in the gene or alterations in methylation status of its promoter were detected, we found a high degree of methylation at CpG islands in intron 1 of EGR2 in cell lines that were expressing this gene at a high level. Moreover, reporter gene experiments revealed that methylated intron 1 had somehow conferred enhancer-like activity. The data imply the existence of a previously unsuspected mechanism of gene expression regulation.

Base Sequence↗

PubMed1998

Alternative splicing of pre-mRNA: developmental consequences and mechanisms of regulation.

Alternative splicing of pre-mRNAs is a powerful and versatile regulatory mechanism that can effect quantitative control of gene expression and functional diversification of proteins. It contributes to major developmental decisions and also to fine tuning of gene function. Genetic and biochemical approaches have identified cis-acting regulatory elements and trans-acting factors that control alternative splicing of specific pre-mRNAs. Both approaches are contributing to an understanding of their mode of action. Some alternative splicing decisions are controlled by specific factors whose expression is highly restricted during development, but others may be controlled by more modest variations in the levels of general factors acting cooperatively or antagonistically. Certain factors play active roles in both constitutive splicing and regulation of alternative splicing. Cooperative and antagonistic effects integrated at regulatory elements are likely to be important for specificity and for finely tuned differences in cell-type-specific alternative splicing patterns.

Alternative Splicing↗

PubMed1994

Developmental stage-specific regulation of atrial natriuretic factor gene transcription in cardiac cells.

Cardiac myocytes undergo a major genetic switch within the first week of postnatal development, when cell division ceases terminally and many cardiac genes are either activated or silenced. We have developed stage-specific cardiocyte cultures to analyze transcriptional control of the rat atrial natriuretic factor (ANF) gene to identify the mechanisms underlying tissue-specific and developmental regulation of this gene in the heart. The first 700 bp of ANF flanking sequences was sufficient for cardiac muscle- and stage-specific expression in both atrial and ventricular myocytes, and a cardiac muscle-specific enhancer was localized between -136 and -700 bp. Deletion of this enhancer markedly reduced promoter activity in cardiac myocytes and derepressed ANF promoter activity in nonexpressing cells. Two distinct domains of the enhancer appeared to contribute differentially to cardiac specificity depending on the differentiation stage of the myocytes. DNase I footprinting of the enhancer domain active in differentiated cells revealed four putative regulatory elements including an A+T-rich region and a CArG element. Deletion mutagenesis and promoter reconstitution assays revealed an important role for the CArG-containing element exclusively in cardiac cells, where its activity was switched on in differentiated myocytes. Transcriptional activity of the ANF-CArG box correlated with the presence of a cardiac- and stage-specific DNA-binding complex which was not recognized by the c-fos serum response element. Thus, the use of this in vitro model system representing stage-specific cardiac development unraveled the presence of different regulatory mechanisms for transcription of the ANF gene during cardiac differentiation and may be useful for studying the regulatory pathways of other genes that undergo switching during cardiac myogenesis.

Animals↗

PubMed1994

New functions of the Drosophila rhomboid gene during embryonic and adult development are revealed by a novel genetic method, enhancer piracy.

Localized expression of the Drosophila rhomboid (rho) gene has been proposed to hyperactivate EGF-Receptor signaling in specific cells during development of the embryo and adult. In this report we use a novel transposon based genetic method, enhancer piracy, to drive ectopic expression of a rho cDNA transgene by endogenous genomic enhancers. Many enhancer piracy transposon-rho insertions cause dominant phenotypes, over half of which cannot be duplicated by ubiquitous expression of rho. Genetic interactions between various dominant enhancer piracy alleles and mutations in the EGF-R/RAS signaling pathway indicate that many of these novel phenotypes result from ectopic activation of EGF-R signaling. Patterned mis-expression of the rho cDNA transgene correlates in several cases with localized dominant enhancer piracy phenotypes. Enhancer piracy lines reveal an unanticipated role for rho in imaginal disc formation and provide the first evidence that mis-expression of rho is sufficient for converting entire intervein sectors into veins. Enhancer piracy may prove to be a general strategy for obtaining dominant alleles of a gene of interest in diverse insects, worms, plants, and potentially in vertebrates such as mice and fish.

Alleles↗

PubMed1997

Cell type-specific chromatin organization of the region that governs directionality of yeast mating type switching.

Switching of mating type in Saccharomyces cerevisiae is directional; MAT alpha cells recombine to transfer information from HMRa while MATa cells switch using the silent cassette at HML alpha. Genetic analysis recently has defined a 700 bp recombination enhancer approximately 29 kb from the left end of chromosome III that is necessary for directionality. The chromatin structure of this region differs strikingly in a- and alpha-cells. Mat alpha2p organizes a 3.7 kb chromatin domain that opposes interaction of trans-acting proteins with the enhancer. In a-cells lacking the alpha2 repressor, two footprinted regions flank an approximately 100 bp section having a unique DNA structure. This structural signature probably reflects interactions of proteins that result in directional mating type switching.

Base Sequence↗

PubMed1989

Regulation of immunoglobulin gene rearrangement and expression.

The molecular genetic events leading to Ig expression and their control formed the topic of a recent EMBO workshop. This report by Michael Taussig, Martin Sims and Ulrich Krawinkel discusses contributions dealing with genes expressed in early pre-B cells, the mechanism of rearrangement, aberrant rearrangements seen in B cells of SCID mice, the feedback control of rearrangement as studied in transgenic mice, the control of Ig expression at the transcriptional and post-transcriptional levels, and class switching.

Animals↗

PubMed1989

Molecular genetics of dopa decarboxylase and biogenic amines in Drosophila.

The gene Ddc encodes two isoforms of the enzyme dopa decarboxylase in Drosophila. These gene products catalyze the final steps in the synthesis of the biogenic amines serotonin and dopamine. This article summarizes recent progress in understanding the tissue- and cell-specific regulation of Ddc, which occurs at both the transcription and alternate splicing levels. In addition, results that are pertinent to understanding the roles of biogenic amines in the neurophysiology of Drosophila are discussed.

Animals↗

PubMed1986

Control of rDNA replication in Tetrahymena involves a cis-acting upstream repeat of a promoter element.

A novel genetic scheme was used to isolate mutants altered in the formation or maintenance of amplified rDNA in the Tetrahymena macronucleus. One such mutant had a cis-acting rDNA mutation that affected the ability of mutant rDNA molecules to replicate in macronuclei in the presence of a wild-type (B strain) rDNA. The mutant rDNA was lost from these heterozygous macronuclei during vegetative cell divisions, although it was maintained normally in the homozygous or hemizygous state. In contrast, wild-type macronuclear rDNA of the C3 strain used to obtain the mutant outreplicated B strain rDNA in B/C3 heterozygote macronuclei. Sequence differences were found between wild-type B and C3 and mutant C3 rDNAs in the replication origin region, changing an upstream repeat of a highly conserved rRNA promoter element. We propose that the various rDNA alleles differentially compete for limiting amounts of trans-acting factors that bind to these enhancer-like repeats and positively regulate rDNA replication.

Animals↗