Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have used the globin family of genes in chicken to study developmental regulation of gene expression, both at the level of individual interaction of trans-acting factors with local promoters and enhancers, and at the level of chromatin structure. Regulation of all members of the alpha- and beta-globin clusters is affected by the erythroid regulatory factor GATA-1. Separate mechanisms exist for regulation of individual members of the family. As an example, we describe the control mechanisms that play a role in the expression of the rho-globin gene, which is expressed only in primitive lineage erythroid cells. In addressing the involvement of chromatin structure in gene activation, we have examined the role of locus control elements, and also considered the way in which RNA polymerase molecules might accommodate to the presence of nucleosomes on transcribed genes.
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PMID:Developmental regulation of globin gene expression. 129 48

Kell is one of the major blood group systems in human erythrocytes. It is a complex system containing a large number of different antigens. Previously we cloned the Kell cDNA, which was predicted to encode an integral membrane protein with 731 amino acids. Now we have isolated overlapping genomic clones and determined the exon-intron structure of the KEL gene; it spans approximately 21.5 kb with its coding sequence being organized in 19 exons that range in size from 63 bp to 288 bp. The size of introns ranges from 93 bp to approximately 6 kb. The donor and acceptor splice sites all conform to the consensus splicing sequences. Exon 1 encodes only the initiation amino acid, methionine, and contains a consensus Sp1 binding site. The single membrane spanning region of Kell protein is encoded in exon 3 and the putative zinc endopeptidase active site is in exon 16. The amino acids encoded by the 19 exons are identical to those of a person with a common Kell phenotype, as determined by RNA polymerase chain reaction of peripheral blood. Amplification of cDNA 5' ends, derived from human fetal liver, indicated three transcription initiation sites located 30, 81, and 120 bp upstream of the initiation codon. The 5' flanking region of KEL from -176 does not contain a TATA sequence, but has possible GATA-1 binding sites and has significant promoter activity when determined by chloramphenicol acetyltransferase activity in K562 cells.
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PMID:Organization of the gene encoding the human Kell blood group protein. 863 75

The Wilms'-tumor gene WT1 may have a different function from a tumor-suppressor gene in some leukemias. Using the 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat leukemia system, we examined whether WT1 expression was involved during leukemogenesis, since this model enabled us to analyze cells altered by DMBA at various stages of leukemogenesis. By the semi-quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) method, WT1 expression was detected in 15 (71%) of 21 DMBA-induced erythroblastic leukemias. Among 15 WT1-expressing leukemias, GATA-1, which is an erythroid-specific transcription factor and might regulate WT1 expression, was also expressed in 13 cases (p < 0.05). On the other hand, WT1 expression was not detected in any normal or early pre-leukemic rats and was detected in 1 of 8 rats in late pre-leukemic stages. These results showed that cells with a high expression level of WT1 tended to develop into leukemia and that WT1 contributed to leukemogenesis in the late stage, suggesting that the expression of WT1 plays an important role in cell proliferation and in maintaining the viability of some leukemia cells.
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PMID:WT1 contributes to leukemogenesis: expression patterns in 7,12-dimethylbenz[a]anthracene (DMBA)-induced leukemia. 925 12

In vertebrates several proteins containing a covalently bound selenocysteine residue have been identified. Among these, selenoprotein P is the most unusual one: depending on the species, 8-12 selenocysteine residues are cotranslationally integrated into the polypeptide chain. The protein was traced in rat plasma, but its role has not been worked out so far. In order to improve our understanding on selenoprotein P we investigated its tissue-specific expression and its genomic DNA. RNA in situ hybridization analyses confirmed the liver-specific expression in mice. Selenoprotein P was also found to be expressed in testis, brain, gut, and hematopoietic cells. The murine selp gene contains five exons within 10.3 kb with a coding sequence restricted to exons 2 to 5. The complete gene including the selp promoter was sequenced. One TATA motif 38 bp upstream to exon 1 suggests transcription of selp by RNA polymerase II. Within the 1116 bp upstream of exon 1 four hepatic nuclear factor 3beta (HNF3beta) binding motifs were found, which is in line with liver-specific expression of selenoprotein P. The expression in hematopoietic cells might be due to multiple GATA-1 motifs. Two BRN-2 motifs suitable for the binding of brain-specific regulatory factors correlated to the selenoprotein P expression in the cerebellum. Selenoprotein P was also expressed in Leydig cells which could be regulated by binding proteins docking to the SRY motifs present in the promoter region.
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PMID:Analysis of the mouse selenoprotein P gene. 968 17

The a- and b-globin gene clusters are subject to several levels of regulation. They are expressed exclusively in the erythroid cells, only during defined periods of development and in a perfectly tuned way, assuring, at any stage of ontogeny, a correct balance in the availability of a- and b-globin chains for hemoglobin assembling. Such a tight control is dependent on regulatory regions of DNA located either in proximity or at great distances from the globin genes in a region characterized by the presence of several DNAse I hypersensitive sites and known as the Locus Control Region. All these sequences exert stimulatory, inhibitory or more complex activities by interacting with transcription factors that bridge these regions of DNA to the RNA polymerase machinery. Many of these factors have now been cloned and the corresponding mouse genes inactivated, shading new light on the metabolic pathways they control. It is increasingly recognized that such factors are organized into hierarchies according to the number of genes and circuits they regulate. Some genes such as GATA-1 and 2 are master regulators that act on large numbers of genes at early stage of differentiation whereas others, like EKLF, stand on the lowest step and control only single or limited number of genes at late stages of differentiation. We will review recent data gathered from expression studies in cell cultures, in transgenic or K.O. murine models as well as from a clinical settings. We will also discuss the development of novel theories on the regulation of the a- and b-globin genes and clusters.
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PMID:Regulation of the globin genes. 1191 23

The hematopoietic transcription factor GATA-1 regulates erythropoiesis and beta-globin expression. Although consensus GATA-1 binding sites exist throughout the murine beta-globin locus, we found that GATA-1 discriminates among these sites in vivo. Conditional expression of GATA-1 in GATA-1-null cells recapitulated the occupancy pattern. GATA-1 induced RNA polymerase II (pol II) recruitment to subregions of the locus control region and to the beta-globin promoters. The hematopoietic factor NF-E2 cooperated with GATA-1 to recruit pol II to the promoters. We propose that only when GATA-1 attracts pol II to the locus control region can pol II access the promoter in a NF-E2-dependent manner.
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PMID:Cooperative activities of hematopoietic regulators recruit RNA polymerase II to a tissue-specific chromatin domain. 1219 59

Sertoli cells isolated from 6-day postpartum mouse testes were conditionally immortalized with the simian virus 40 large tumor antigen gene (SV40-LTAg) under the control of a promoter inducible with ponasterone A, an analog of ecdysone. This strategy produced 2 cell lines, which exhibited mixed phenotypes. We first tested the conditional expression of the LTAg gene in the presence or absence of ponasterone A. The results showed that both cell lines expressed LTAg when the inducer was present in the culture media. When ponasterone A was removed, the majority of the cells died. After 60 generations, however, the continued expression of LTAg in the absence of the hormone indicated that unknown changes may have occurred in the genome of the cells. One of the cell lines was further subcloned, resulting in 7 new lines exhibiting a morphology resembling that of Sertoli cells in tissue culture. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on RNA collected from each cell line in order to determine which cells were phenotypically similar to Sertoli cells in vivo. All cell lines expressed the products of the Sertoli cell-specific genes stem cell factor (SCF) and sulfated glycoprotein-2 (SGP-2), in addition to alpha-inhibin, GATA-1, and steroidogenic factor-1. Further, the lines express growth and differentiation factors known to act upon germ cells in vivo and in vitro such as leukemia inhibitory factor (LIF), transforming growth factor beta (TGF-beta), and basic fibroblast growth factor (bFGF). Moreover, when used as feeder layers in cocultures, at least 2 of these lines are able to maintain the viability of type A spermatogonia for at least 7 days and to support the first steps of spermatogonial differentiation.
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PMID:Establishment and characterization of neonatal mouse sertoli cell lines. 1251 93

The developmentally regulated mammalian beta-globin genes are activated by a distant locus control region/enhancer. To understand the role of chromatin remodeling complexes in this activation, we used stably replicated chromatin templates, in which transcription activation of the human embryonic epsilon-globin gene depends on the tandem Maf-recognition elements (MAREs) within the beta-globin locus control region HS2 enhancer, to which the erythroid factor NF-E2 binds. The HS2 MAREs are required for nucleosome mobilization and histone hyperacetylation at the distant promoter. Nucleosome mobilization also requires the promoter TATA box, and is independent of histone hyperacetylation. In contrast, promoter hyperacetylation requires the promoter GATA-1, and CACC-factor activator motifs, as well as the TATA box. ChIP analysis reveals that NF-E2 is associated with the active epsilon-globin promoter, which lacks an NF-E2 binding sequence, in a TATA box and HS2/MARE-dependent fashion. NF-E2 association with the epsilon-globin promoter coincides with that of RNA polymerase II at both regulatory sites. The results emphasize MARE-TATA box interactions in the recruitment of complexes modifying promoter chromatin for transcription activation and imply close physical interaction between widely separated regulatory sequences mediated through these sites.
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PMID:A major role for the TATA box in recruitment of chromatin modifying complexes to a globin gene promoter. 1277 26

Megakaryopoiesis is the process by which hematopoietic stem cells in the bone marrow differentiate into mature megakaryocytes. The expression of megakaryocytic genes during megakaryopoiesis is controlled by specific transcription factors. Fli-1 and GATA-1 transcription factors are required for development of megakaryocytes and promoter analysis has defined in vitro functional binding sites for these factors in several megakaryocytic genes, including GPIIb, GPIX, and C-MPL. Herein, we utilize chromatin immunoprecipitation to examine the presence of Ets-1, Fli-1, and GATA-1 on these promoters in vivo. Fli-1 and Ets-1 occupy the promoters of GPIIb, GPIX, and C-MPL genes in both Meg-01 and CMK11-5 cells. Whereas GPIIb is expressed in both Meg-01 and CMK11-5 cells, GPIX and C-MPL are only expressed in the more differentiated CMK11-5 cells. Thus, in vivo occupancy by an Ets factor is not sufficient to promote transcription of some megakaryocytic genes. GATA-1 and Fli-1 are both expressed in CMK11-5 cells and co-occupy the GPIX and C-MPL promoters. Transcription of all three megakaryocytic genes is correlated with the presence of acetylated histone H3 and phosphorylated RNA polymerase II on their promoters. We also show that exogenous expression of GATA-1 in Meg-01 cells leads to the expression of endogenous c-mpl and gpIX mRNA. Whereas GPIIb, GPIX, and C-MPL are direct target genes for Fli-1, both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. In contrast, GPIIb expression appears to be independent of GATA-1 in Meg-01 cells.
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PMID:Ets-dependent regulation of target gene expression during megakaryopoiesis. 1546 56

The 5'-HS4 chicken beta-globin insulator functions as a positional enhancer blocker on chromatinized episomes in human cells, blocking the HS2 enhancer of the human beta-globin locus control region from activating a downstream epsilon-globin gene. 5'-HS4 interrupted formation of a domain of histone H3 and H4 acetylation encompassing the 6-kb minilocus and inhibited transfer of RNA polymerase from the enhancer to the gene promoter. We found that the enhancer blocking phenotype was amplified when the insulated locus contained a weakened HS2 enhancer in which clustered point mutations eliminated interaction of the transcription factor GATA-1. The GATA-1 mutation compromised recruitment of histone acetyltransferases and RNA polymerase II to HS2. Enhancer blocking correlated with a significant depletion of nucleosomes in the core region of the insulator as revealed by micrococcal nuclease and DNase I digestion studies. Nucleosome depletion at 5'-HS4 was dependent on interaction of the insulator protein CCCTC-binding factor (CTCF) and was required for enhancer blocking. These findings provide evidence that a domain of active chromatin is formed by spreading from an enhancer to a target gene and can be blocked by a nucleosome-free gap in an insulator.
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PMID:Enhancer blocking by chicken beta-globin 5'-HS4: role of enhancer strength and insulator nucleosome depletion. 1687 59


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