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)

Nucleosomes must be deacetylated behind elongating RNA polymerase II to prevent cryptic initiation of transcription within the coding region. RNA polymerase II signals for deacetylation through the methylation of histone H3 lysine 36 (H3K36), which provides the recruitment signal for the Rpd3S histone deacetylase complex (HDAC). The recognition of methyl H3K36 by Rpd3S requires the chromodomain of its Eaf3 subunit. Paradoxically, Eaf3 is also a subunit of the NuA4 acetyltransferase complex, yet NuA4 does not recognize methyl H3K36 nucleosomes. In Saccharomyces cerevisiae, we found that methyl H3K36 nucleosome recognition by Rpd3S also requires the plant homeobox domain (PHD) of its Rco1 subunit. Thus, the coupled chromo and PHD domains of Rpd3S specify recognition of the methyl H3K36 mark, demonstrating the first combinatorial domain requirement within a protein complex to read a specific histone code.
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PMID:Combined action of PHD and chromo domains directs the Rpd3S HDAC to transcribed chromatin. 1751 Mar 66

Transcription corepressors are general regulators controlling the expression of genes involved in multiple signaling pathways and developmental programs. Repression is mediated through mechanisms including the stabilization of a repressive chromatin structure over control regions and regulation of Mediator function inhibiting RNA polymerase II activity. Using whole-genome arrays we show that the Arabidopsis thaliana corepressor LEUNIG, a member of the GroTLE transcription corepressor family, regulates the expression of multiple targets in vivo. LEUNIG has a role in the regulation of genes involved in a number of different physiological processes including disease resistance, DNA damage response, and cell signaling. We demonstrate that repression of in vivo LEUNIG targets is achieved through histone deacetylase (HDAC)-dependent and -independent mechanisms. HDAC-dependent mechanisms involve direct interaction with HDA19, a class 1 HDAC, whereas an HDAC-independent repression activity involves interactions with the putative Arabidopsis Mediator components AtMED14/SWP and AtCDK8/HEN3. We suggest that changes in chromatin structure coupled with regulation of Mediator function are likely to be utilized by LEUNIG in the repression of gene transcription.
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PMID:The transcription corepressor LEUNIG interacts with the histone deacetylase HDA19 and mediator components MED14 (SWP) and CDK8 (HEN3) to repress transcription. 1752 32

Butyrate is a histone deacetylase inhibitor (HDACi) with anti-neoplastic properties, which theoretically reactivates epigenetically silenced genes by increasing global histone acetylation. However, recent studies indicate that a similar number or even more genes are down-regulated than up-regulated by this drug. We treated hepatocarcinoma HepG2 cells with butyrate and characterized the levels of acetylation at DNA-bound histones H3 and H4 by ChIP-chip along the ENCODE regions. In contrast to the global increases of histone acetylation, many genomic regions close to transcription start sites were deacetylated after butyrate exposure. In order to validate these findings, we found that both butyrate and trichostatin A treatment resulted in histone deacetylation at selected regions, while nucleosome loss or changes in histone H3 lysine 4 trimethylation (H3K4me3) did not occur in such locations. Furthermore, similar histone deacetylation events were observed when colon adenocarcinoma HT-29 cells were treated with butyrate. In addition, genes with deacetylated promoters were down-regulated by butyrate, and this was mediated at the transcriptional level by affecting RNA polymerase II (POLR2A) initiation/elongation. Finally, the global increase in acetylated histones was preferentially localized to the nuclear periphery, indicating that it might not be associated to euchromatin. Our results are significant for the evaluation of HDACi as anti-tumourogenic drugs, suggesting that previous models of action might need to be revised, and provides an explanation for the frequently observed repression of many genes during HDACi treatment.
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PMID:Butyrate mediates decrease of histone acetylation centered on transcription start sites and down-regulation of associated genes. 1756 91

RNA polymerase II transcribes most eukaryotic genes. Photobleaching studies have revealed that living Chinese hamster ovary cells expressing the catalytic subunit of the polymerase tagged with the green fluorescent protein contain a large rapidly exchanging pool of enzyme, plus a smaller engaged fraction; genetic complementation shows this tagged polymerase to be fully functional. We investigated how transcriptional inhibitors--some of which are used therapeutically--affect the engaged fraction in living cells using fluorescence loss in photobleaching; all were used at concentrations that have reversible effects. Various kinase inhibitors (roscovitine, DRB, KM05283, alsterpaullone, isoquinolinesulfonamide derivatives H-7, H-8, H-89, H-9), proteasomal inhibitors (lactacystin, MG132), and an anti-tumour agent (cisplatin) all reduced the engaged fraction; an intercalator (actinomycin D), two histone deacetylase inhibitors (trichostatin A, sodium butyrate), and irradiation with ultra-violet light all increased it. The polymerase proves to be both a sensitive sensor and effector of the response to these inhibitors.
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PMID:Photobleaching reveals complex effects of inhibitors on transcribing RNA polymerase II in living cells. 1757 37

The homeodomain transcription factor Crx is required for expression of many photoreceptor genes in the mammalian retina. The mechanism by which Crx activates transcription remains to be determined. Using protein-protein interaction assays, Crx was found to interact with three co-activator proteins (complexes): STAGA, Cbp and p300, all of which possess histone acetyl-transferase (HAT) activity. To determine the role of Crx-HAT interactions in target gene chromatin modification and transcriptional activation, quantitative RT-PCR and chromatin immunoprecipitation were performed on Crx target genes, rod and cone opsins, in developing mouse retina. Although cone opsins are transcribed earlier than rhodopsin during development, the transcription of each gene is preceded by the same sequence of events in their promoter and enhancer regions: (i) binding of Crx, followed by (ii) binding of HATs, (iii) the acetylation of histone H3, then (iv) binding of other photoreceptor transcription factors (Nrl and Nr2e3) and RNA polymerase II. In Crx knockout mice (Crx(-/-)), the association of HATs and AcH3 with target promoter/enhancer regions was significantly decreased, which correlates with aberrant opsin transcription and photoreceptor dysfunction in these mice. Similar changes to the opsin chromatin were seen in Y79 retinoblastoma cells, where opsin genes are barely transcribed. These defects in Y79 cells can be reversed by expressing a recombinant Crx or applying histone deacetylase inhibitors. Altogether, these results suggest that one mechanism for Crx-mediated transcriptional activation is to recruit HATs to photoreceptor gene chromatin for histone acetylation, thereby inducing and maintaining appropriate chromatin configurations for transcription.
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PMID:Crx activates opsin transcription by recruiting HAT-containing co-activators and promoting histone acetylation. 1765 71

The effects of the RNA polymerase II (RNAPII) translocation inhibitors alpha amanitin and 5,6-dichloro-1-beta-D-ribobenzimidazole (DRB) and an siRNA targeting p300 on the presence of RNAPII, p300, hyperacetylated H4 and H3 and unmodified H4 and H3 in transcribing simian virus 40 (SV40) minichromosomes were determined. Following treatment with alpha amanitin we observed a profound reduction in the occupancy of the promoter by RNAPII, the loss of p300 from chromatin fragments containing RNAPII, and an increase in the amount of unmodified H4 and H3 associated with the RNAPII. Treatment with DRB had little effect on the presence of RNAPII or p300 but also resulted in a significant increase in the amount of unmodified H4 and H3 present in chromatin fragments associated with RNAPII. Following treatment with a p300 small interfering RNA (siRNA), we observed a significant decrease in late transcription and a corresponding reduction in the amounts of p300 and hyperacetylated histones associated with the transcribing SV40 minichromosomes. We conclude that in transcribing SV40 minichromosomes histone hyperacetylation and deacetylation is dependent upon the presence of p300 and an as yet unknown histone deacetylase associated with the RNAPII complex that occurs coordinately as the RNAPII complex moves through a nucleosome.
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PMID:Histone hyperacetylation during SV40 transcription is regulated by p300 and RNA polymerase II translocation. 1765 52

Dysregulation of DNA methyltransferase (DNMT)1 expression is associated with cellular transformation, and inhibition of DNMT1 exerts antitumorigenic effects. Here, we report that DNMT1 abnormally expressed in HeLa cells is downregulated by a histone deacetylase (HDAC) inhibitor apicidin, which is correlated with induction of repressive histone modifications on the promoter site. Apicidin selectively represses the expression of DNMT1 among DNMTs in HeLa cells, independent of cell cycle arrest at G0/G1. Furthermore, apicidin causes a significant reduction in the recruitment of RNA polymerase II into the promoter. Chromatin immunoprecipitation analysis shows that even though apicidin causes global hyperacetylation of histone H3 and H4, localized deacetylation of histone H3 and H4 occurs at the E2F binding site, which is accompanied by the recruitment of pRB and the replacement of P/CAF with HDAC1 into the sites. In addition, K4-trimethylated H3 on nucleosomes associated with the transcriptional start site is depleted following apicidin treatment, whereas repressive markers, K9- and K27-trimethylation of H3 are enriched on the site. The downregulation of DNMT1 expression seems to require de novo protein synthesis, because the apicidin effect is antagonized by cycloheximide treatment. Moreover, knock down of DNMT1 with siRNA induces the apoptosis of HeLa cells, indicating that downregulation of DNMT1 might be a good strategy for therapeutics of human cervix cancer. Collectively, our findings will provide a mechanistic rationale for the use of HDAC inhibitors in cancer therapeutics.
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PMID:Histone deacetylase inhibitor apicidin downregulates DNA methyltransferase 1 expression and induces repressive histone modifications via recruitment of corepressor complex to promoter region in human cervix cancer cells. 1782 6

The histone deacetylase inhibitor trichostatin A (TsA) potently induces 5-lipoxygenase (5-LO) promoter activity in reporter gene assays as well as 5-LO mRNA expression. We identified two proximal Sp1/Sp3 binding sites in the 5-LO gene promoter mediating the TsA effect in both 5-LO-negative HeLa cells and in 5-LO expressing Mono Mac 6 (MM6) cells, the tandem GC-boxes, by contrast, were not important for the TsA effect. TsA neither altered the protein expression levels of Sp1/Sp3 nor of the histone deacetylases HDAC1/2, nor did it apparently change the protein complex formation by these factors. Also, treatment of cells with TsA did not change the binding affinity of Sp1/Sp3 in cell extracts, as tested by DAPA analysis using probes containing the proximal GC boxes. However, in the living cell TsA induced Sp1, Sp3 and RNA polymerase II recruitment to the 5-LO promoter without changing the acetylation status of histone protein H4. Cotransfection studies suggest that both Sp1 and Sp3 can mediate the TsA effect. This is the first report demonstrating that Sp3 is involved in the regulation of 5-LO promoter activity. In summary, we show that TsA increases 5-LO promoter activity by the enhanced recruitment of Sp1 and Sp3 to the 5-LO promoter.
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PMID:The histone deacetylase inhibitor trichostatin A mediates upregulation of 5-lipoxygenase promoter activity by recruitment of Sp1 to distinct GC-boxes. 1789 44

Snf1, the yeast AMP kinase homolog, is essential for derepression of glucose-repressed genes that are activated by Adr1. Although required for Adr1 DNA binding, the precise role of Snf1 is unknown. Deletion of histone deacetylase genes allowed constitutive promoter binding of Adr1 and Cat8, another activator of glucose-repressed genes. In repressed conditions, at the Adr1-and Cat8-dependent ADH2 promoter, partial chromatin remodeling had occurred, and the activators recruited a partial preinitiation complex that included RNA polymerase II. Transcription did not occur, however, unless Snf1 was activated, suggesting a Snf1-dependent event that occurs after RNA polymerase II recruitment. Glucose regulation persisted because shifting to low glucose increased expression. Glucose repression could be completely relieved by combining the three elements of 1) chromatin perturbation by mutation of histone deacetylases, 2) activation of Snf1, and 3) the addition of an Adr1 mutant that by itself confers only weak constitutive activity.
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PMID:A poised initiation complex is activated by SNF1. 1797 63

The balance between antiapoptotic and proapoptotic proteins of the Bcl-2 family is critical in determining the fate of T cells in response to death stimuli. Proapoptotic genes, such as bax, are generally regulated by the p53 family of transcription factors, whereas NF-kappaB subunits can activate the transcription of antiapoptotic Bcl-2 members. Here, we show that CD28 activation protects memory T cells from irradiation-induced apoptosis by both upregulating bcl-xL and inhibiting bax gene expression. We found that p73, but not p53, binds to and trans-activates the bax gene promoter in irradiated T cells. The activation of RelA/NF-kappaB subunit in CD28 costimulated T cells and its binding onto the bax gene promoter results in suppression of bax transcription and decrease in both p73 and RNA polymerase II recruitment in vivo. RelA recruitment on the bax gene promoter is also accompanied by the lost of p300 binding and the parallel appearance of histone deacetylase-1-containing complexes. These findings identify RelA/NF-kappaB as a critical regulator of T-cell survival by affecting the balance of Bcl-2 family members.
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PMID:RelA/NF-kappaB recruitment on the bax gene promoter antagonizes p73-dependent apoptosis in costimulated T cells. 1803 90


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