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)

Histone acetylation is associated with transcriptional activation of many genes. However, the role of acetylation in transcriptional regulation of heat shock protein genes (hsp) still remains an obscure issue. Here we examined the effects of histone deacetylase inhibitors (HDIs), trichostatin A, and sodium butyrate, on changes in acetylation level of core histones and on expression of hsp22 gene in Drosophila melanogaster. The results showed that both HDIs elevated the acetylation level of histone H3. By using the chromatin immunoprecipitation, we located the HDI-induced H3 hyperacetylation at both the promoter and the downstream of RNA polymerase II of the transcribing hsp22 gene. Meanwhile, the elevated acetylation level increased the accessibility of heat shock factor to target cis-acting regulatory sites. We conclude that histone acetylation stimulates the transcription initiation and promotes the transcription elongation, thereby up-regulating both basal and inducible expression of hsp22 in D. melanogaster.
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PMID:Histone acetylation regulates both transcription initiation and elongation of hsp22 gene in Drosophila. 1560 42

Histone methylation and the enzymes that mediate it are important regulators of chromatin structure and gene transcription. In particular, the histone H3 lysine 36 (K36) methyltransferase Set2 has recently been shown to associate with the phosphorylated C-terminal domain (CTD) of RNA polymerase II (RNAPII), implying that this enzyme has an important role in the transcription elongation process. Here we show that a novel domain in the C terminus of Set2 is responsible for interaction between Set2 and RNAPII. This domain, termed the Set2 Rpb1 interacting (SRI) domain, is encompassed by amino acid residues 619 to 718 in Set2 and is found to occur in a number of putative Set2 homologs from Schizosaccharomyces pombe to humans. Unexpectedly, BIACORE analysis reveals that the SRI domain binds specifically, and with high affinity, to CTD repeats that are doubly modified (serine 2 and serine 5 phosphorylated), indicating that Set2 association across the body of genes requires a specific pattern of phosphorylated RNAPII. Deletion of the SRI domain not only abolishes Set2-RNAPII interaction but also abolishes K36 methylation in vivo, indicating that this interaction is required for establishing K36 methylation on chromatin. Using 6-azauracil (6AU) as an indicator of transcription elongation defects, we found that deletion of the SRI domain conferred a strong resistance to this compound, which was identical to that observed with set2 deletion mutants. Furthermore, yeast strains carrying set2 alleles that are catalytically inactive or yeast strains bearing point mutations at K36 were also found to be resistant to 6AU. These data suggest that it is the methylation by Set2 that affects transcription elongation. In agreement with this, we have determined that deletion of SET2, its SRI domain, or amino acid substitutions at K36 result in an alteration of RNAPII occupancy levels over transcribing genes. Taken together, these data indicate K36 methylation, established by the SRI domain-mediated association of Set2 with RNAPII, plays an important role in the transcription elongation process.
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PMID:A novel domain in Set2 mediates RNA polymerase II interaction and couples histone H3 K36 methylation with transcript elongation. 1579 14

Histone methylation is regarded as a stable modification important in the epigenetic regulation of gene expression. Transcriptionally active chromatin is methylated at H3-K4 whereas repressed chromatin is methylated at H3-K9. To investigate the role of histone methylation in an acute inflammatory response, A549 cells were treated with IL-1beta and/or the methylase inhibitor 5-azacytidine (5-aza), and histone H3-K4 methylation levels and transcription of secretory leukocyte protease inhibitor (SLPI) were measured. IL-1beta stimulation enhanced histone H3-K4 tri-methylation across the SLPI coding region at 24h. In parallel, IL-1beta enhanced recruitment of RNA polymerase II to the SLPI gene. 5-aza attenuated both H3-K4 tri-methylation and RNA polymerase II recruitment to a similar extent resulting in reduced SLPI mRNA and protein levels. These data suggest that in addition to epigenetic regulation of constitutive SLPI expression, H3-K4 tri-methylation may play a role in stimulated SLPI expression by modulating RNA polymerase II recruitment and subsequent gene transcription.
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PMID:5-Azacytidine suppresses RNA polymerase II recruitment to the SLPI gene. 1584 63

Expression of endothelial nitric-oxide synthase (eNOS) mRNA is highly restricted to the endothelial cell layer of medium to large sized arterial blood vessels. Here we assessed the chromatin environment of the eNOS gene in expressing and nonexpressing cell types. Within endothelial cells, but not a variety of nonendothelial cells, the nucleosomes that encompassed the eNOS core promoter and proximal downstream coding regions were highly enriched in acetylated histones H3 and H4 and methylated lysine 4 of histone H3. This differentially modified chromatin domain was selectively associated with functionally competent RNA polymerase II complexes. Endothelial cells were particularly enriched in acetylated histone H3 lysine 9, histone H4 lysine 12, and di- and tri-methylated lysine 4 of histone H3 at the core promoter. Histone modifications at this region, which we have previously demonstrated to exhibit cell-specific DNA methylation, were functionally relevant to eNOS expression. Inhibition of histone deacetylase activity by trichostatin A increased acetylation of histones H3 and H4 at the eNOS proximal promoter in nonexpressing cell types and led to increased steady-state eNOS mRNA transcript levels. H3 lysine 4 methylation was also essential for eNOS expression, since treatment of endothelial cells with methylthioadenosine, a known lysine 4 methylation inhibitor, decreased eNOS RNA levels, H3 lysine 4 methylation, and RNA polymerase II loading at the eNOS proximal promoter. Importantly, methylthioadenosine also prevented the trichostatin A-mediated increase in eNOS mRNA transcript levels in nonendothelial cells. Taken together, these findings provide strong evidence that the endothelial cell-specific expression of eNOS is controlled by cell-specific histone modifications.
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PMID:The expression of endothelial nitric-oxide synthase is controlled by a cell-specific histone code. 1587 70

The PI3K/Akt pathway plays a critical role in the regulation of gene expression induced by numerous stimuli. p300, a transcriptional coactivator, acts in concert with transcription factors to facilitate gene expression. Here, we show that Akt is activated and translocated to the nucleus in response to tumor necrosis factor alpha. Nuclear Akt associates with p300 and phosphorylates its Ser-1834 both in vivo and in vitro. The phosphorylation induces recruitment of p300 to the ICAM-1 promoter, leading to the acetylation of histones in chromatin and association with the basal transcriptional machinery RNA polymerase II. These two events facilitate ICAM-1 gene expression and are abolished by the p300 S1834A mutant, inhibitors of PI3K/Akt, or small interfering RNA of Akt. Histone acetylation is attributed to the Akt-enhanced intrinsic histone acetyltransferase (HAT) activity of p300 and its association with another HAT, p/CAF. Our study provides a new insight into the molecular mechanism by which Akt promotes the transcriptional potential of p300.
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PMID:Akt phosphorylation of p300 at Ser-1834 is essential for its histone acetyltransferase and transcriptional activity. 1602 95

Histone-lysine methylation is linked to transcriptional regulation and the control of epigenetic inheritance. Lysine residues can be mono-, di-, or trimethylated, and it has been suggested that each methylation state of a given lysine may impart a unique biological function. In yeast, histone H3 lysine 4 (K4) is mono-, di-, and trimethylated by the Set1 histone methyltransferase. Previous studies show that Set1 associates with RNA polymerase II and demarcates transcriptionally active genes with K4 trimethylation. To determine whether K4 trimethylation might be selectively regulated, we screened a library of yeast deletion mutants associated with transcriptional regulation and chromatin function. We identified BUR2, a cyclin for the Bur1/2 (BUR) cyclin-dependent protein kinase, as a specific regulator of K4 trimethylation. Surprisingly, BUR also regulated H2B monoubiquitylation, whereas other K4 methylation states and H3 lysine 79 (K79) methylation were unaffected. Synthetic genetic array (SGA) and transcription microarray analyses of a BUR2 mutant revealed that BUR is functionally similar to the PAF, Rad6, and Set1 complexes. These data suggest that BUR acts upstream of these factors to control their function. In support, we show that recruitment of the PAF elongation complex to genes is significantly impaired in a BUR2 deletion. Our data reveal a novel function for the BUR kinase in transcriptional regulation through the selective control of histone modifications.
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PMID:BUR kinase selectively regulates H3 K4 trimethylation and H2B ubiquitylation through recruitment of the PAF elongation complex. 1604 Feb 46

Histone methylation plays an important role in eukaryotic transcriptional regulation. A number of histone methyltransferases (HMTases) with distinct functions have been identified. The HSPC069/HYPB gene was originally isolated from the human hematopoietic stem/progenitor cells (HSPCs), and it was also identified as a huntingtin interacting protein, implicated in the pathogenesis of Huntington disease (HD). However, its biochemical function is poorly understood. Here we report the structural and functional characterization of the huntingtin interacting protein B (HYPB). 1) The triplicate AWS-SET-PostSET domains mediate a histone H3 lysine 36 specific HMTase activity. 2) A low charged region that is rich in glutamine and proline has been characterized as a novel transcriptional activation domain. The structural features of this region are evolutionarily conserved in vertebrates. 3) Coimmunoprecipitation assays indicate that HYPB protein associates with hyperphosphorylated RNA polymerase II (RNAPII) but not the unphosphorylated form. Furthermore, the RNAPII-association region of HYPB protein has been identified to encompass the C-terminal 142 amino acids. Thus, our results suggest that HYPB HMTase may coordinate histone methylation and transcriptional regulation in mammals and open perspective for the further study of the potential roles of HYPB protein in hematopoiesis and pathogenesis of HD.
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PMID:Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase. 1611 27

Histone acetylation regulates gene expression, yet the functional contributions of the numerous histone acetyltransferases (HATs) to gene expression and their relationships with each other remain largely unexplored. The central role of the putative HAT-containing TAF1 subunit of TFIID in gene expression raises the fundamental question as to what extent, if any, TAF1 contributes to acetylation in vivo and to what extent it is redundant with other HATs. Our findings herein do not support the basic tenet that TAF1 is a major HAT in Saccharomyces cerevisiae, nor do we find that TAF1 is functionally redundant with other HATs, including Gcn5, Elp3, Hat1, Hpa2, Sas3, and Esa1, which is in contrast to previous conclusions regarding Gcn5. Our findings do reveal that of these HATs, only Gcn5 and Esa1 contribute substantially to gene expression genome wide. Interestingly, histone acetylation at promoter regions throughout the genome does not require TAF1 or RNA polymerase II, indicating that most acetylation is likely to precede transcription and not depend upon it. TAF1 function has been linked to Bdf1, which binds TFIID and acetylated histone H4 tails, but no linkage between TAF1 and the H4 HAT Esa1 has been established. Here, we present evidence for such a linkage through Bdf1.
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PMID:Genome-wide relationships between TAF1 and histone acetyltransferases in Saccharomyces cerevisiae. 1653 21

Histone modifications such as methylation and acetylation in the chromatin surrounding a gene are thought to regulate transcriptional activity. In this study, to determine whether dynamic changes occur in histone modification on the loci of stress-responsive genes in plants, we chose rice submergence-inducible ADH1 and PDC1 genes. When submerged, the rice ADH1 and PDC1 genes were activated in a biphasic manner: the first and second inductions occurred after approximately 2 and 12 h of submergence, respectively. Their expression was transcriptionally induced as shown by increased binding of RNA polymerase II to the ADH1 and PDC1 loci during submergence. The Lys4 residues of the histone H3 proteins (H3-K4s) at both the 5'- and 3'-coding regions of ADH1 and PDC1 were found to change from a di-methylated state to a tri-methylated state at the first induction period. On the other hand, acetylation of H3 increased throughout ADH1 and PDC1 genes at the later induction period. The methylation and acetylation levels recovered to the initial levels during re-aeration. Treatment of seedlings with a histone deacetylase (HDAC) inhibitor, trichostatin A, increased acetylation of histones H3 and association of RNA polymerase II on the ADH1 and PDC1 loci, thereby increasing transcript levels of ADH1 and PDC1. Together, these results showed dynamic and reversible changes of histone H3-K4 methylation and H3 acetylation in stress-responsive genes in a higher plant in response to the appearance or disappearance of an environmental stress.
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PMID:Dynamic and reversible changes in histone H3-Lys4 methylation and H3 acetylation occurring at submergence-inducible genes in rice. 1677 28

Histone acetyltransferases/deacetylases contribute to the activation or inactivation of transcription by modifying the structure of chromatin. Here we examined the effects of histone deacetylase inhibitors (HDIs), trichostatin A, and sodium butyrate on hsp70 gene transcriptional regulation in Drosophila. The chromatin immunoprecipitation assays revealed that HDI treatments induced the hyperacetylation of histone H3 at the promoter and the transcribing regions of hsp70 gene, increased the accessibility of heat-shock factor to target heat-shock element, and promoted the RNA polymerase II-mediated transcription. Moreover, the quantitative real-time PCR confirmed that the HDI-induced hyperacetylation of histone H3 enhanced both the basal and the inducible expression of hsp70 mRNA level. In addition, the acetylation level of histone H3 at the promoter exhibited a fluctuated change upon the time of heat shock. These experimental data implicated a causal link between histone acetylation and enhanced transcription initiation of hsp70 gene in Drosophila.
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PMID:Effects of histone deacetylase inhibitors on transcriptional regulation of the hsp70 gene in Drosophila. 1677 28


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