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Epigenetic priming of a pre-B cell-specific enhancer through binding of Sox2 and Foxd3 at the ESC stage.
Liber D, Domaschenz R, Holmqvist PH, Mazzarella L, Georgiou A, Leleu M, Fisher AG, Labosky PA, Dillon N
(2010) Cell Stem Cell 7: 114-26
MeSH Terms: Animals, Cell Line, Cells, Cultured, Chromatin Immunoprecipitation, DNA Footprinting, Embryonic Stem Cells, Enhancer Elements, Genetic, Epigenesis, Genetic, Forkhead Transcription Factors, Hemangioblasts, Immunoglobulin Light Chains, Surrogate, Mice, Oligonucleotide Array Sequence Analysis, Precursor Cells, B-Lymphoid, Protein Binding, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, SOXB1 Transcription Factors, SOXC Transcription Factors
Show Abstract · Added August 2, 2010
Modifications to the core histones are thought to contribute to ESC pluripotency by priming tissue-specific promoters and enhancers for later activation. However, it is unclear how these marks are targeted in ESCs and maintained during differentiation. Here, we show that the ESC factor Sox2 targets H3K4 methylation to monovalent and bivalent domains. In ESCs, Sox2 contributes to the formation of a monovalent mark at an enhancer in the pro/pre-B cell-specific lambda5-VpreB1 locus. Binding of Foxd3 suppresses intergenic transcription of the enhancer and surrounding sequences. In pro-B cells, enhancer activity is dependent on the Sox and Fox binding sites, and the enhancer is bound by Sox4, which is required for efficient expression of lambda5. Our results lead us to propose a factor relay model whereby ESC factors establish active epigenetic marks at tissue specific elements before being replaced by cell type-specific factors as cells differentiate.
Copyright (c) 2010 Elsevier Inc. All rights reserved.
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19 MeSH Terms
Molecular basis of the targeting of topoisomerase II-mediated DNA cleavage by VP16 derivatives conjugated to triplex-forming oligonucleotides.
Duca M, Guianvarc'h D, Oussedik K, Halby L, Garbesi A, Dauzonne D, Monneret C, Osheroff N, Giovannangeli C, Arimondo PB
(2006) Nucleic Acids Res 34: 1900-11
MeSH Terms: Antineoplastic Agents, Phytogenic, DNA, DNA Damage, DNA Footprinting, DNA Topoisomerases, Type II, Drug Delivery Systems, Enzyme Inhibitors, Etoposide, Humans, Oligodeoxyribonucleotides, Topoisomerase II Inhibitors
Show Abstract · Added March 5, 2014
Human topoisomerase II (topo II) is the cellular target for a number of widely used antitumor agents, such as etoposide (VP16). These agents 'poison' the enzyme and induce it to generate DNA breaks that are lethal to the cell. Topo II-targeted drugs show a limited sequence preference, triggering double-stranded breaks throughout the genome. Circumstantial evidence strongly suggests that some of these breaks induce chromosomal translocations that lead to specific types of leukaemia (called treatment-related or secondary leukaemia). Therefore, efforts are ongoing to decrease these secondary effects. An interesting option is to increase the sequence-specificity of topo II-targeted drugs by attaching them to triplex-forming oligonucleotides (TFO) that bind to DNA in a highly sequence-specific manner. Here five derivatives of VP16 were attached to TFOs. The active topo II poisons, once linked, induced cleavage 13-14 bp from the triplex end where the drug was attached. The use of triple-helical DNA structures offers an efficient strategy for targeting topo II-mediated cleavage to DNA specific sequences. Finally, drug-TFO conjugates are useful tools to investigate the mechanistic details of topo II poisoning.
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11 MeSH Terms
An androgen-dependent upstream enhancer is essential for high levels of probasin gene expression.
Zhang J, Gao N, Kasper S, Reid K, Nelson C, Matusik RJ
(2004) Endocrinology 145: 134-48
MeSH Terms: Androgen-Binding Protein, Androgens, Animals, Binding Sites, Breast Neoplasms, Cell Line, Tumor, DNA Footprinting, DNA Mutational Analysis, Enhancer Elements, Genetic, Gene Expression Regulation, Genes, Reporter, Humans, Male, Promoter Regions, Genetic, Prostate, Prostatic Neoplasms, Rats, Transcriptional Activation
Show Abstract · Added June 11, 2010
Previously we reported that a small rat probasin (PB) promoter (-426 to +28 bp, -426PB) would target androgen- regulated prostate-specific expression in transgenic mice. Later we demonstrated that a large (L) fragment (-10806 to +28 bp, LPB) of the PB promoter would target high levels of gene expression to the prostate in transgenic mice. These results suggested that optimal transcription of the PB gene depended on the presence of enhancer regions upstream of the proximal promoter. To identify these enhancers, the LPB fragment was sequenced and the enhancer activities of restriction fragments were characterized in cell lines. Two nonconventional androgen receptor binding sites (ARBSs), ARBS-3 and ARBS-4, in an upstream androgen-dependent enhancer of the PB gene were identified. One site functions as a weak steroid response element in both LNCaP and MCF-7 cells; another site acts as a strong steroid response element, which preferentially responds to androgen and is preferentially activated in LNCaP cells. These two new ARBSs interact in a cooperative manner with the previously described androgen response region (ARR) (defined by -244 to -96 bp) that contains ARBS-1; ARBS-2; and two lower-affinity ARR binding sites, G-1 and G-2 sites. We conclude that the context in which the ARR binding sites are present is pivotal in determining their effect on transcriptional regulation. Thus, the -705/+28 PB promoter contains a second ARR, PB enhancer element (-705/-426 PB), in addition to the first described ARR. The PB promoter creates a model that contains six AR binding sites that function in a cooperative manner for maximum androgen-regulated prostate-specific gene transcription.
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18 MeSH Terms
Molecular characterization of Saccharomyces cerevisiae TFIID.
Sanders SL, Garbett KA, Weil PA
(2002) Mol Cell Biol 22: 6000-13
MeSH Terms: Animals, DNA, DNA Footprinting, Humans, Macromolecular Substances, Molecular Weight, Promoter Regions, Genetic, Protein Subunits, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Transcription Factor TFIIA, Transcription Factor TFIID, Transcription Factors, Transcription Factors, TFII, Transcription, Genetic
Show Abstract · Added March 5, 2014
We previously defined Saccharomyces cerevisiae TFIID as a 15-subunit complex comprised of the TATA binding protein (TBP) and 14 distinct TBP-associated factors (TAFs). In this report we give a detailed biochemical characterization of this general transcription factor. We have shown that yeast TFIID efficiently mediates both basal and activator-dependent transcription in vitro and displays TATA box binding activity that is functionally distinct from that of TBP. Analyses of the stoichiometry of TFIID subunits indicated that several TAFs are present at more than 1 copy per TFIID complex. This conclusion was further supported by coimmunoprecipitation experiments with a systematic family of (pseudo)diploid yeast strains that expressed epitope-tagged and untagged alleles of the genes encoding TFIID subunits. Based on these data, we calculated a native molecular mass for monomeric TFIID. Purified TFIID behaved in a fashion consistent with this calculated molecular mass in both gel filtration and rate-zonal sedimentation experiments. Quite surprisingly, although the TAF subunits of TFIID cofractionated as a single complex, TBP did not comigrate with the TAFs during either gel filtration chromatography or rate-zonal sedimentation, suggesting that TBP has the ability to dynamically associate with the TFIID TAFs. The results of direct biochemical exchange experiments confirmed this hypothesis. Together, our results represent a concise molecular characterization of the general transcription factor TFIID from S. cerevisiae.
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15 MeSH Terms
Transcriptional regulation of the cellular retinoic acid binding protein I gene in F9 teratocarcinoma cells.
Means AL, Thompson JR, Gudas LJ
(2000) Cell Growth Differ 11: 71-82
MeSH Terms: Animals, Base Sequence, Cell Differentiation, Cell Nucleus, DNA Footprinting, Enhancer Elements, Genetic, Fibroblasts, Gene Expression Regulation, Neoplastic, Mice, Molecular Sequence Data, Neoplasm Proteins, Promoter Regions, Genetic, RNA, Messenger, RNA, Neoplasm, Receptors, Retinoic Acid, Teratocarcinoma, Transcription, Genetic, Transfection, Tretinoin, Tumor Cells, Cultured
Show Abstract · Added July 19, 2013
Retinoic acid (RA) induces the differentiation of many murine teratocarcinoma cell lines such as F9 and P19. In F9 cells, the level of the cellular retinoic acid binding protein I (CRABP I) mRNA is greatly reduced after exposure of the cultured cells to exogenous RA. In P19 cells, the level of CRABP I mRNA is greatly increased after RA exposure. We have identified a 176-bp region in the murine CRABP I promoter, between -2.9 and -2.7 kb 5' of the start site of transcription, which acts as an enhancer in undifferentiated F9 stem cells and through which RA effects inhibition of CRABP I transcription. Within this region are two footprinted sites at -2763 and -2834. This 176-bp regulatory region does not function to enhance CRABP I transcription in P19 stem cells. Several DNA sequences within these two footprinted regions bind proteins from F9 nuclear extracts but not from P19 nuclear extracts (e.g., FP1B, FP1A, and FP2B), as assessed by gel shift assays. This 176-bp CRABP I genomic region has not been sequenced previously and functionally analyzed in cultured cells because it was not present in the murine CRABP I clones used for the promoter analyses reported earlier by another laboratory. The function of this enhancer may be to reduce the expression of the CRABP I gene in specific embryonic cell types in order to regulate the amount of RA to which the cells are exposed.
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20 MeSH Terms
Selective activation of the probasin androgen-responsive region by steroid hormones.
Kasper S, Rennie PS, Bruchovsky N, Lin L, Cheng H, Snoek R, Dahlman-Wright K, Gustafsson JA, Shiu RP, Sheppard PC, Matusik RJ
(1999) J Mol Endocrinol 22: 313-25
MeSH Terms: Androgen-Binding Protein, Androgens, Base Sequence, Chloramphenicol O-Acetyltransferase, DNA Footprinting, Gene Expression Regulation, Glucocorticoids, Humans, Molecular Sequence Data, Receptors, Androgen, Receptors, Glucocorticoid, Tumor Cells, Cultured
Show Abstract · Added June 11, 2010
Glucocorticoid and androgen receptors have been shown to function through the same palindromic glucocorticoid response element (GRE) and yet have differential effects on gene transcription. In this study, we examined the functional and structural relationship of the androgen and glucocorticoid receptors with the androgen responsive region (ARR) of the probasin (PB) gene containing two androgen receptor binding sites, ARBS-1 and ARBS-2. Transfection studies indicated that one copy of each cis-acting DNA element was essential for maximal androgen-induced chloramphenicol acetyltransferase (CAT) activity and that androgen selectivity was maintained when multiple copies of the minimal wild type (wt) androgen responsive region containing both ARBS-1 and ARBS-2 (-244 to -96) were subcloned in front of the thymidine kinase promoter. Furthermore, replacing the androgen response region with 1, 2 or 3 copies of either ARBS-1 or ARBS-2 restored less than 4% of the biological activity seen with the wt PB ARR. Multiple copies of either ARBS-1 or ARBS-2 did not result in glucocorticoid-induced CAT gene activity. By comparison, 1 or 2 copies of the tyrosine aminotransferase (TAT) GRE, as well as the mouse mammary tumour virus GRE, were strong inducers of CAT activity in response to both androgen and glucocorticoid treatment. In addition, band shift assays demonstrated that although the synthetic glucocorticoid receptor, GR-DNA binding domain (GR-DBD), and the synthetic androgen receptor, AR2, could interact with the TAT GRE (dissociation constants Kd of 63.9 and 14.1 respectively), only AR2 but not GR-DBD binding could be detected on ARBS-1 and ARBS-2. Our findings provide further evidence that androgen-induced regulation of gene transcription can occur through androgen-specific DNA binding sites that are distinct from the common GRE.
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12 MeSH Terms
Genetic tests of the role of Abf1p in driving transcription of the yeast TATA box bindng protein-encoding gene, SPT15.
Schroeder SC, Weil PA
(1998) J Biol Chem 273: 19884-91
MeSH Terms: Binding Sites, DNA Footprinting, DNA-Binding Proteins, Fungal Proteins, Gene Expression Regulation, Fungal, Genes, Fungal, Genes, Reporter, Models, Genetic, RNA, Messenger, Saccharomyces cerevisiae Proteins, TATA Box, TATA-Box Binding Protein, Temperature, Transcription Factors, Transcriptional Activation
Show Abstract · Added March 5, 2014
In this report we describe studies which utilized yeast strains bearing gain and loss of function alleles of ABF1 in order to attempt to directly implicate Abf1p in modulating transcription of the TBP-encoding gene, SPT15, in vivo. We found that overexpression of Abf1p in a yeast cell increased transcription of the TBP-encoding gene and that this stimulation depended upon the exact sequence of the Abf1p binding site (ABF1) present in the gene. Further, in a yeast strain expressing a temperature sensitive form of Abf1p, occupancy of the chromosomal ABF1 site in the TBP-encoding gene was immediately lost following a temperature shift. Both results suggest that Abf1p drives transcription of the TBP-encoding gene. Surprisingly though we found that continuous ABF1 cis-element occupancy by Abf1p was not acutely required for normal levels of transcription of either the TBP-encoding gene or other "Abf1p-driven" genes tested. We propose a model to explain these results and suggest mechanisms by which Abf1p could activate gene transcription.
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15 MeSH Terms
Androgen regulation of the human ornithine decarboxylase promoter in prostate cancer cells.
Bai G, Kasper S, Matusik RJ, Rennie PS, Moshier JA, Krongrad A
(1998) J Androl 19: 127-35
MeSH Terms: Androgens, Animals, Binding Sites, Cell Differentiation, DNA Footprinting, Dogs, Enzyme Activation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Male, Ornithine Decarboxylase, Ornithine Decarboxylase Inhibitors, Promoter Regions, Genetic, Prostatic Neoplasms, Protein Kinase C, Receptors, Androgen, Tumor Cells, Cultured
Show Abstract · Added June 11, 2010
We studied the response of the human ornithine decarboxylase (ODC) promoter to androgen in human prostate cancer cell lines. In the well-differentiated, androgen-sensitive human prostate cancer line LNCaP, a genomic ODC promoter fragment that includes putative androgen response elements was suppressed by androgen. In contrast, the androgen-regulated probasin promoter was induced by androgens. The ODC promoter was also induced by cotransfected androgen receptor in the poorly differentiated, androgen-insensitive human prostate cancer cell line PPC-1. We examined the effects of cotransfected mutant androgen receptors containing the LNCaP mutation or DNA-binding mutations. All cotransfected androgen receptors switched the ODC androgen response from suppression to induction in LNCaP cells. Gel-shift and DNA footprint assays demonstrated androgen receptor binding to an ODC sequence that does not contain a consensus androgen response element. Deletion of the sequence abolished androgen suppression of the ODC promoter. We propose a model of pleiotropic gene regulation by androgen that requires a regulatory balance between androgen receptor and a transcription factor binding to the nonconsensus androgen response element.
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18 MeSH Terms
Binding of phosphorylated Sp1 protein to tandem Sp1 binding sites regulates alpha2 integrin gene core promoter activity.
Zutter MM, Ryan EE, Painter AD
(1997) Blood 90: 678-89
MeSH Terms: Antigens, CD, Base Sequence, Binding Sites, Cell Differentiation, Consensus Sequence, DNA Footprinting, Enhancer Elements, Genetic, Humans, Integrin alpha2, Integrins, Megakaryocytes, Nuclear Proteins, Promoter Regions, Genetic, Recombinant Proteins, Sp1 Transcription Factor, Transcription, Genetic, Transfection, Tumor Cells, Cultured
Show Abstract · Added February 16, 2014
The alpha2beta1 integrin, a collagen/laminin receptor, is expressed by a variety of cell types, including epithelial cells, mesenchymal cells, and hematopoietic cells. To understand the molecular mechanisms that regulate expression of the alpha2beta1, integrin in cells with megakaryocytic differentiation, we characterized the 5' flanking region of the alpha2 integrin gene and identified three distinct regulatory regions, including a core promoter, a silencer, and megakaryocyte enhancers in the distal 5' flank (Zutter et al, Blood 96:3006, 1995 and Zutter et al, J Biol Chem 269:463, 1994). We now focus on the core promoter of the alpha2 integrin gene located between bp -30 and -92 that is required for transcriptional activity of the alpha2 integrin gene. Sequence analysis identified two Sp1 consensus sites and a potential AP2 site. Gel retardation assays showed that nuclear proteins from uninduced K562 cells and K562 cells induced to become megakaryocytic bound specifically to the core promoter region (bp -30 to bp -92) producing two DNA-protein complexes. In addition, nuclear extracts from cells induced along the megakaryocyte lineage produced a selective increase in the slower migrating complex. Site-directed mutagenesis of the 5', the 3', or both Sp1 binding sites suggested that both Sp1 binding sites are required for full promoter activity and for DNA-protein complex formation. DNA footprinting also showed specific protection of the 5' Sp1 site by nuclear extracts from uninduced K562 cells and protection of both the 5' and the 3' Sp1 sites by nuclear extracts from induced K562 cells. Sp1 protein-DNA complex formation was dependent on Sp1 phosphorylation. The faster migrating DNA-protein complex was enhanced by dephosphorylation; the slower migrating DNA-protein complex was diminished or lost.
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18 MeSH Terms
Activity of the distal positive element of the peripherin gene is dependent on proteins binding to an Ets-like recognition site and a novel inverted repeat site.
Chang L, Thompson MA
(1996) J Biol Chem 271: 6467-75
MeSH Terms: Animals, Base Sequence, Binding Sites, Binding, Competitive, Cell Differentiation, Chromosome Mapping, DNA, DNA Footprinting, Eye Proteins, Intermediate Filament Proteins, Membrane Glycoproteins, Molecular Sequence Data, Mutagenesis, Site-Directed, Nerve Tissue Proteins, Neuropeptides, PC12 Cells, Peripherins, Protein Binding, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-ets, Rats, Repetitive Sequences, Nucleic Acid, Transcription Factors
Show Abstract · Added March 5, 2014
The peripherin gene, encoding a neuron-specific intermediate filament protein, is transcriptionally induced when PC12 cells begin to terminally differentiate into neurons in response to nerve growth factor. Previously we identified two regulatory sequences of the peripherin gene: a proximal negative element (centered at -173), which prevents peripherin expression in undifferentiated PC12 cells, and a distal positive region (-2660 to -2308) necessary for full induction of peripherin in differentiated PC12 cells (Thompson, M., Lee, E. Lawe, D., Gizang-Ginsberg, E., and Ziff, E. (1992) Mol. Cell. Biol. 12,2501-2513). Here we define a distal positive element (DPE, -2445 to -2337) within the distal positive region. Methylation interference footprinting of the DPE identified DNA-protein contact points at a novel inverted repeat sequence (AACCACTGGTT) and an Ets-like recognition sequence (CAGGAG). Functional analysis using site-directed mutagenesis demonstrates that both sites are necessary for the activity of the DPE. In addition, ternary complex formation at the DPE is dependent on both sites. Antibody competition assays confirm that an Ets family member participates in the DNA-protein complex. We have indirect evidence that the inverted repeat binding protein and the Ets-related protein interact directly with each other. Finally, we demonstrate that the DPE is constitutively active and that neuron-specific regulation of peripherin expression may be due to interaction with distal and proximal negative regulatory elements.
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23 MeSH Terms