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At least 19 recordsLinked to original sources
PubMed1990

A set of human putative lymphocyte G0/G1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes.

Lymphocyte G0/G1 switch genes (G0S genes) are potential oncogenes and may regulate, be regulated by, or be coordinately regulated with, latent lymphotropic viruses. To identify these genes, a cDNA library was prepared from blood mononuclear cells that had been cultured for 2 hr with a T-cell mitogen (lectin) and cycloheximide. Eight differentially hybridizing recombinants were characterized by RNA and DNA blotting and sequencing. One cDNA (G0S7) corresponded to the oncogene c-fos. Another cDNA (G0S19) was homologous (70%) to a cDNA encoding a murine inhibitor of stem cell proliferation (the cytokine MIP1 alpha) and, less closely, to other members of the "small inducible" secreted protein-encoding gene family. Whereas cDNA hybridization to genomic DNA blots indicated a small subfamily of G0S19 genes, simple patterns of bands indicated that most cDNAs, including G0S30 cDNA, corresponded to single-copy genes. The 3' noncoding sequence of G0S30 cDNA was homologous (87-89%) to the 3' noncoding sequences of certain rodent genes (NGFI-A, Krox24, EGR1) that encode zinc finger proteins (putative transcriptional regulators). This degree of evolutionary conservation suggests an important function for the 3' noncoding region. The 3' noncoding regions of some cDNAs contained the TTATTTAT (mRNA destabilization) element. The corresponding RNAs each formed doublets in agarose gels. Previous studies of c-fos RNA from HeLa cells indicate that this is due to cycloheximide-dependent stabilization of poly(A) tails. Our results reveal the power of cycloheximide enrichment in isolating what would appear to be significant low-abundance mRNAs.

Base Sequence↗
PubMed1992

The protein sequence and some intron positions are conserved between the switching gene swi10 of Schizosaccharomyces pombe and the human excision repair gene ERCC1.

The switching gene swi10+ has a function in mating-type switching as well as in the repair of radiation damages. We have cloned the genomic swi10+ gene by functional complementation of the switching defect of the swi10-154 mutant. The swi10+ gene is not essential for viability. The DNA sequence revealed an open reading frame of 759 nucleotides interrupted by three introns of 127, 52 and 60 bp, respectively. The positions of intron I as well as of intron III of swi10 are evolutionary conserved in comparison to the introns III and IV of the human ERCC1 gene. The analysis of cDNA clones isolated by PCR amplification confirmed the structure of the swi10 gene. The putative Swi10 protein has homologies to the human and mouse ERCC1 protein, to Rad10 of Saccharomyces cerevisiae and to parts of UvrA and UvrC of E. coli. All these proteins are essential components for excision repair of damaged DNA. The Swi10 protein contains a putative DNA binding domain previously found in other proteins. Northern blot experiments and the analyses of cDNA clones indicate that intron I of the swi10 gene is not efficiently spliced.

Amino Acid Sequence↗
PubMed1992

Individual stage selector element mutations lead to reciprocal changes in beta- vs. epsilon-globin gene transcription: genetic confirmation of promoter competition during globin gene switching.

Biochemical and genetic analysis of the embryonic to adult beta-like globin gene switch in chickens has led to the hypothesis that competition between the promoters of the cis-linked epsilon- and beta-globin genes for interaction with a shared enhancer mediates the developmental changes in expression of beta-globin protein isotypes. To test specific predictions of this promoter competition model, a sensitive RNA/polymerase chain reaction assay has been used to investigate the effects of individual beta-globin promoter mutations on expression of the two linked genes in transiently transfected erythroid cells. Mutations that attenuated adult beta-globin transcription resulted concomitantly in a proportional increase in expression of the embryonic epsilon-globin gene. Consistent with the model, mutations disrupting the binding sites for either of two adult stage-specific transcription factors (NF-E4 and beta CTF) indicate that these sites are essential both for induction of beta-globin gene expression and for indirect suppression (through promoter competition) of epsilon-globin transcription in definitive (adult) erythroid cells. These results provide direct evidence that stage-specific transcription factors affect the equilibrium existing between multiple interacting globin cis-regulatory elements. We conclude that promoter competition is an important mechanism through which developmental regulation of chicken beta-globin gene switching is achieved and that such competitive interactions may prove to be generally applicable to the regulation of a variety of other temporally or spatially restricted gene expression patterns.

Animals↗
PubMed1988

Butyrate infusions in the ovine fetus delay the biologic clock for globin gene switching.

The switch from fetal to adult hemoglobin expression is regulated in many mammalian species by a developmental clock-like mechanism and determined by the gestational age of the fetus. Prolonging fetal globin gene expression is of considerable interest for therapeutic potential in diseases caused by abnormal beta-globin genes. Butyric acid, which is found in increased plasma concentrations in infants of diabetic mothers who have delayed globin gene switching, was infused into catheterized fetal lambs in utero during the time of the normal globin gene switch period. The globin gene switch was significantly delayed in three of four butyrate-treated fetuses compared with controls and was entirely prevented in one fetus in whom the infusion was begun before the globin switch was under way. These data provide a model for investigating and arresting the biologic clock of hemoglobin switching.

Animals↗
PubMed1989

Butyric acid modulates developmental globin gene switching in man and sheep.

The developmental switch from production of fetal (gamma) to adult (beta) globin occurs on a normally set biologic clock which proceeds even if the adult (beta) globin genes are defective. Preventing or reversing the globin gene switch would be beneficial for subjects with abnormal beta globin genes. We have now identified a class of agents which, when present in elevated plasma concentrations during gestation, appears to inhibit the gamma beta globin gene switch in developing humans. Further investigation has shown that butyric acid and related compounds can increase gamma globin and decrease beta globin expression in erythroid cells cultured from subjects with diseases of abnormal beta globin. Butyrate compounds were therefore infused in an in vivo fetal animal model, and the globin switch was inhibited in most and reversed in some fetal lambs. These data suggest that inhibiting expression of abnormal beta globin genes may be possible in future generations. Histone modification may be a mechanism of action involved. The developmental switch from production of gamma globin to beta globin results in significant morbidity when the beta globin genes are defective. The globin switch has therefore been extensively studied, appearing to be set on a biologic clock and proceeding despite the site of blood production and solely on the basis of gestational age. We previously found that this developmental gene switch is delayed in human fetuses developing in the presence of maternal diabetes. A number of metabolites present in abnormal concentrations in these infants were therefore tested for effects on globin expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed1991

Developmental regulation of fetal to adult globin gene switching in human fetal erythroid x mouse erythroleukemia cell hybrids.

Human fetal erythroid x murine erythroleukemia cell hybrids undergo human fetal (gamma) to adult (beta) globin gene switching in vitro under the control of a mechanism located on human chromosome 11. We investigated whether this mechanism acts in cis or in trans by preparing hybrid cells containing marked fragments of the gamma and beta genes known to switch in transgenic mice. In these cells the chromosomally introduced human globin locus undergoes the fetal to adult globin gene switch. In contrast, the marked globin gene fragments were expressed at all stages of hybrid development. These results suggest that either the mechanism of switching acts in cis or that sequences present in the chromosomal globin locus but missing from the transfected globin gene fragments mediate its action.

Animals↗
PubMed1992

Mating-type gene switching in Saccharomyces cerevisiae.

The study of yeast mating-type (MAT) gene switching has provided insights into several aspects of the regulation of gene expression. MAT switching is accomplished by a highly programmed site-specific homologous recombination event in which mating-type-specific sequences at MAT are replaced by alternative DNA sequences copied from one of two unexpressed donors. The mating-type system has also provided an opportunity to study both the genetic regulation of gene silencing by alterations in chromatin structure, and the basis of preferential recombination between a recipient of genetic information and one of several possible donors.

Alleles↗
PubMed1990

Stopping the biologic clock for globin gene switching.

The developmental switch from production of fetal (gamma) to adult (beta) globin occurs on a normally set biologic clock which proceeds even if expression of the adult (beta) globin genes is defective and produces little or no protein, as in the beta-thalassemias. Preventing or reversing the globin gene switch could provide a way of keeping the abnormal globin genes "silent" and maintaining expression of the fetal globin gene. We have identified a class of agents which, when present in elevated plasma concentrations during gestation, inhibits the gamma----beta-globin gene switch in developing humans. Further investigation has shown that butyric acid and related compounds can increase gamma-globin and decrease beta-globin expression in cultured erythroid cells of patients with beta-thalassemia. Butyrate compounds were therefore infused in an in vivo fetal animal model, and the globin switch was inhibited and even reversed in some fetal lambs. Histone hyperacetylation, which maintains active chromatin structure, and an effect on the gamma-globin promoter appear to be mechanisms of action involved. These data suggest that inhibiting expression of abnormal beta-globin genes by pharmacologic means may in the future be possible for treatment of individuals with beta-globin disorders.

Anemia, Sickle Cell↗
PubMed1990

Human gamma- to beta-globin gene switching in transgenic mice.

Previous studies demonstrated correct tissue- and temporal-specific expression of human gamma- and beta-globin genes in transgenic mice; however, expression was extremely low. When the erythroid-specific DNase I super-hypersensitive (HS) sites that are normally located upstream of the human beta-globin locus were fused individually to gamma- or beta-globin genes, expression increased to endogenous mouse globin levels but temporal specificity was lost. In contrast, when the HS sequences were combined with fragments containing both gamma- and beta-globin genes, correct developmental regulation was restored. We suggest that human gamma- to beta-globin gene switching during development results from competition of individual globin gene family members for interaction with the HS sequences and that factors influencing these competitive interactions determine temporal specificity.

Animals↗
PubMed1992

Properties of B cell stage specific and ubiquitous nuclear factors binding to immunoglobulin heavy chain gene switch regions.

The Ig heavy chain (IgH) constant region (CH) class switch is manifested by DNA deletions which exchange the C mu gene of a functional VDJ-CH rearrangement for a C gamma, C epsilon or C alpha gene. Repetitive sequences (S regions) 5' of each CH gene mediate CH gene switch recombination by an illegitimate mechanism. S mu can be subdivided into S mu 5' (non-repetitive) and S mu 3' (repetitive) components with recombination occurring in either part. Here, we describe the properties of ubiquitous and B cell stage specific S mu binding factors NFS mu-U1 and NFS mu-B1 respectively. U1 only bound to S mu 5' sequences, and B1 to S mu 5', S mu 3' sequences and to other S regions with varying affinities. DMS and OP-Cu footprinting revealed the sequence AAAAAGCATGGCTGA in the U1 site while the B1 S mu 5' site overlapped the 3' end of the U1 binding site and also contained additional 3' flanking S mu repeat motifs (GAGCTGAGATGGGTGGGCT). Binding site competition assays reveal that NFS mu-B1 is either very related or identical to S alpha BP (described by Waters et al., Mol. Cell Biol. 9:5594, 1989) and BSAP (identified by Barberis et al., Genes Devl. 4:849, 1990) which were shown to bind to two sequences upstream of the S alpha repeats and within the promoters of sea urchin histone genes respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Histone gene switching in murine erythroleukemia cells is differentiation specific and occurs without loss of cell cycle regulation.

We investigated the expression characteristics of the fully replication-dependent (FRD) and the partially replication-dependent (PRD) histone gene variants by measuring changes in steady-state mRNA levels during hexamethylene bisacetamide (HMBA)-induced differentiation of murine erythroleukemia (MEL) cells. Between 24 and 60 h after induction, there was a dramatic switch in histone gene expression, such that the ratio of PRD to FRD transcripts increased severalfold over that found in uninduced MEL cells. We demonstrated that this gene switching was not simply a partial or complete uncoupling of PRD gene expression from DNA synthesis. PRD and FRD transcript levels were regulated coordinately upon treatment of uninduced or induced MEL cells with inhibitors of DNA synthesis, protein synthesis, or both. Using several criteria, we were unable to detect any difference in PRD and FRD gene expression under any conditions except in cells undergoing differentiation. MEL cells were arrested at a precommitment stage of differentiation by induction with HMBA in the presence of dexamethasone (DEX). If DEX was subsequently removed, DNA synthesis resumed, the cells underwent commitment, and histone gene switching was observed. In contrast, if both DEX and HMBA were removed, DNA synthesis still resumed, but commitment did not occur and no gene switching was observed. These results imply that histone gene switching is intimately related to the differentiation process.

Animals↗
PubMed1991

Globin gene switching: a paradigm or what?

The delineation of the beta-globin locus control region has led to a new understanding of the developmental regulation of the beta-globin gene cluster. It now seems that globin gene switching is effected through the sequential and mutually exclusive interaction of the locus control region with the embryonic, fetal and adult stage specific globin genes.

Animals↗
PubMed1991

A human putative lymphocyte G0/G1 switch gene containing a CpG-rich island encodes a small basic protein with the potential to be phosphorylated.

Genes actively involved in the G0/G1 switch (G0S genes) may be differentially expressed during the lectin-induced switch of lymphocytes from the G0 to the G1 phases of the cell cycle. This paper presents studies of G0S2, a member of a set of putative G0S genes, for which cDNAs were cloned and selected on the basis of differential cDNA hybridization. G0S2 mRNA increases transiently within 1-2 hr of the addition of lectin or cycloheximide to cultured blood mononuclear cells. Comparison of a nearly full-length cDNA sequence with the corresponding genomic sequence reveals one small intron and an open reading frame in the second exon. The derived 103-amino-acid basic protein has two potential alpha-helical domains separated by a hydrophobic region with the potential to generate turns and assume a beta-sheet conformation. Consistent with involvement in the G0/G1 switch, the protein contains potential sites for phosphorylation by protein kinase C and casein kinase II. The gene contains a CpG-rich island suggesting expression in the germ line. An upstream segment contains tandem dinucleotide repeats (CT)19/(CA)16. There is a suitably located TATA box, but potential sites for CCAAT-box binding factors are far upstream, embedded in a 42-nucleotide repeat element. Potential sites for transcription factors AP1, AP2, and AP3 are consistent with rapid transcriptional activation in response to inducing agents.

Amino Acid Sequence↗
PubMed1988

Sex-lethal, a Drosophila sex determination switch gene, exhibits sex-specific RNA splicing and sequence similarity to RNA binding proteins.

The switch gene, Sex-lethal (Sxl), controls sexual development and dosage compensation. It must be active in females and inactive in males throughout development. Analysis of Sxl cDNAs shows that this on/off regulation may be explained by differential RNA splicing; only female transcripts appear to encode functional products, whereas all male transcripts contain an exon that truncates the open reading frame. The functional female product shows sequence similarities with ribonucleoproteins, suggesting that it is an RNA binding protein. Thus, we propose that Sxl encodes a factor that interacts with both its own pre-mRNA (accounting for positive autoregulation) and that of downstream genes to confer female-specific splicing. In this way, a single, simple mechanism could account for both the maintenance and expression of the sexually determined state.

Amino Acid Sequence↗
PubMed1988

DNA methylation: a secondary event in globin gene switching?

Changes in gamma-globin gene methylation accompany the fetal to adult globin switch in man. Using somatic cell hybrids made by fusing mouse erythroleukemia and human fetal erythroid cells, we asked whether methylation is a cause or a consequence of gamma-gene inactivation during development. These hybrids initially express human gamma-globin but switch with time in culture to adult globin gene production. In hybrids before the switch, the gamma-genes are unmethylated. After completion of the switch, the hybrids contain methylated gamma-globin genes. However, during the time that the gamma----beta switch is occurring, hybrids are found that no longer express gamma-globin, yet still possess unmethylated gamma-globin genes. This suggests that methylation is not a primary event in gamma-gene inactivation during human development.

Adult↗
PubMed1990

Developmental regulation of human fetal-to-adult globin gene switching in transgenic mice.

Transgenic mice containing a human fetal (gamma-) or adult (beta-) globin gene linked to the beta-globin gene locus activation region (LAR) express the gene throughout development. By contrast, transgenic mice containing LAR linked to both a fetal and an adult globin gene display the normal developmental switch from fetal to adult gene expression. This suggests that the human fetal-to-adult globin gene switch is controlled through a mutually exclusive interaction between LAR and either the gamma- or beta-globin gene, resulting in the expression of only one gene at any given moment.

Animals↗
PubMed1989

MB-02 cells undergo fetal to adult globin gene switching in response to erythropoietin.

The recently described MB-02 human cell line requires Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) for continuous growth and terminally differentiates into enucleate, hemoglobinized cells in response to erythropoietin. Here, analysis of globin production now demonstrates that uninduced MB-02 cells produce alpha globin and the fetal globin chains G gamma and A gamma in a ratio of 1:3. Addition of erythropoietin results in de novo synthesis of beta globin chains and a marked increase in total Hb/cell. Thus, the MB-02 cell line partially recapitulates the fetal to adult globin switch that occurs during erythroid and human fetal development and provides a new clonal human erythroid progenitor system for investigating the biochemical and molecular events involved in globin gene switching.

Cell Line↗
PubMed1992

The switching gene swi6 affects recombination and gene expression in the mating-type region of Schizosaccharomyces pombe.

The products of 11 switching (swi) genes are required for efficient mating-type (MT) switching in homothallic (h90) strains of Schizosaccharomyces pombe. The MT region of h90 comprises three cassette genes: the expression site mat1:1 and two silent loci, mat2:2 and mat3:3. Besides reducing MT switching, the swi6 mutation leads to deletions in the MT region caused by intrachromosomal cross-overs between two paired cassettes. These deletions only arise if DNA double-strand breaks are present at mat1:1, which initiate MT switching. Furthermore, swi6 allows meiotic recombination in the K region, a region of 16 kb between mat2:2 and mat3:3; in wild-type strains no recombination occurs in K. swi6 also allows the simultaneous expression of two different cassettes in the same haploid cell. Thus swi6 may have an influence on the general chromatin structure in the MT region.

Blotting, Southern↗