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

---

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

At telomeric heterochromatin in yeast, the Sir protein complex spreads from Rap1 sites to silence adjacent genes. This cascade is believed to occur when Sir2, an NAD(+)-dependent enzyme, deacetylates histone H3 and H4 N termini, in particular histone H4 K16, enabling more Sir protein binding. Lysine 56 of histone H3 is located at the entry-exit points of the DNA superhelix surrounding the nucleosome, where it may control DNA compaction. We have found that K56 substitutions disrupt silencing severely without decreasing Sir protein binding at the telomere. Our in vitro and in vivo data indicate that Sir2 deacetylates K56 directly in telomeric heterochromatin to compact chromatin and prevent access to RNA polymerase and ectopic bacterial dam methylase. Since the spread of Sir proteins is necessary but not sufficient for silencing, we propose that silencing occurs when Sir2 deacetylates H3 K56 to close the nucleosomal entry-exit gates, enabling compaction of heterochromatin.
...
PMID:Sir2 deacetylates histone H3 lysine 56 to regulate telomeric heterochromatin structure in yeast. 1788 63

Inflammatory activation of the endothelium by Chlamydophila pneumoniae infection has been implicated in the development of chronic vascular lesions and coronary heart disease by seroepidemiological and animal studies. We tested the hypothesis that C. pneumoniae induced inflammatory gene expression is regulated by Rho-GTPase-related histone modifications. C. pneumoniae infection induced the liberation of proinflammatory interleukin-6, interleukin-8, granulocyte colony-stimulating factor, macrophage inflammatory protein-1beta, granulocyte/macrophage colony-stimulating factor, and interferon-gamma by human endothelial cells. Cytokine secretion was reduced by simvastatin and the specific Rac1 inhibitor NSC23766 but was synergistically enhanced by inhibitors of histone deacetylases trichostatin A and suberoylanilide hydroxamic acid. Infection of endothelial cells with viable C. pneumoniae, but not exposure to heat-inactivated C. pneumoniae or infection with C. trachomatis, induced acetylation of histone H4 and phosphorylation and acetylation of histone H3. Pretreatment of C. pneumoniae-infected cells with simvastatin or NSC23766 reduced global histone modifications as well as specific modifications at the il8 gene promoter, as shown by chromatin immunoprecipitation. Reduced recruitment of nuclear factor kappaB p65/RelA as well as of RNA polymerase II was observed in statin-treated cells. Taken together, Rac1-mediated histone modifications seem to play an important role in C. pneumoniae-induced cytokine production by human endothelial cells.
...
PMID:Simvastatin reduces Chlamydophila pneumoniae-mediated histone modifications and gene expression in cultured human endothelial cells. 1843 97

Posttranslational histone modifications are crucial for the modulation of chromatin structure and regulation of transcription. Bromodomains present in many chromatin-associated proteins recognize acetylated lysines in the unstructured N-terminal regions of histones. Here, we report that the double bromodomain proteins Brd2 and Brd3 associate preferentially in vivo with hyperacetylated chromatin along the entire lengths of transcribed genes. Brd2- and Brd3-associated chromatin is significantly enriched in H4K5, H4K12, and H3K14 acetylation and contains relatively little dimethylated H3K9. Both Brd2 and Brd3 allowed RNA polymerase II to transcribe through nucleosomes in a defined transcription system. Such activity depended on specific histone H4 modifications known to be recognized by the Brd proteins. We also demonstrate that Brd2 has intrinsic histone chaperone activity and is required for transcription of the cyclin D1 gene in vivo. These data identify proteins that render nucleosomes marked by acetylation permissive to the passage of elongating RNA polymerase II.
...
PMID:The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. 1840 26

The FACT complex is a conserved cofactor for RNA polymerase II elongation through nucleosomes. FACT bears histone chaperone activity and contributes to chromatin integrity. However, the molecular mechanisms behind FACT function remain elusive. Here we report biochemical, structural, and mutational analyses that identify the peptidase homology domain of the Schizosaccharomyces pombe FACT large subunit Spt16 (Spt16-N) as a binding module for histones H3 and H4. The 2.1-A crystal structure of Spt16-N reveals an aminopeptidase P fold whose enzymatic activity has been lost. Instead, the highly conserved fold directly binds histones H3-H4 through a tight interaction with their globular core domains, as well as with their N-terminal tails. Mutations within a conserved surface pocket in Spt16-N or posttranslational modification of the histone H4 tail reduce interaction in vitro, whereas the globular domains of H3-H4 and the H3 tail bind distinct Spt16-N surfaces. Our analysis suggests that the N-terminal domain of Spt16 may add to the known H2A-H2B chaperone activity of FACT by including a H3-H4 tail and H3-H4 core binding function mediated by the N terminus of Spt16. We suggest that these interactions may aid FACT-mediated nucleosome reorganization events.
...
PMID:The FACT Spt16 "peptidase" domain is a histone H3-H4 binding module. 1857 87

Legionella pneumophila causes severe pneumonia. Acetylation of histones is thought to be an important regulator of gene transcription, but its impact on L. pneumophila-induced expression of proinflammatory cytokines is unknown. L. pneumophila strain 130b induced the expression of the important chemoattractant IL-8 and genome-wide histone modifications in human lung epithelial A549 cells. We analyzed the IL-8-promoter and found that histone H4 was acetylated and H3 was phosphorylated at Ser(10) and acetylated at Lys(14), followed by transcription factor NF-kappaB. Recruitment of RNA polymerase II to the IL-8 promoter corresponded with increases in gene transcription. Histone modification and IL-8 release were dependent on p38 kinase and NF-kappaB pathways. Legionella-induced IL-8 expression was decreased by histone acetylase (HAT) inhibitor anacardic acid and enhanced by histone deacetylase (HDAC) inhibitor trichostatin A. After Legionella infection, HATs p300 and CREB-binding protein were time-dependently recruited to the IL-8 promoter, whereas HDAC1 and HDAC5 first decreased and later reappeared at the promoter. Legionella specifically induced expression of HDAC5 but not of other HDACs in lung epithelial cells, but knockdown of HDAC1 or 5 did not alter IL-8 release. Furthermore, Legionella-induced cytokine release, promoter-specific histone modifications, and RNA polymerase II recruitment were reduced in infection with flagellin-deletion mutants. Legionella-induced histone modification as well as HAT-/HDAC-dependent IL-8 release could also be shown in primary lung epithelial cells. In summary, histone acetylation seems to be important for the regulation of proinflammatory gene expression in L. pneumophila infected lung epithelial cells. These pathways may contribute to the host response in Legionnaires' disease.
...
PMID:Histone acetylation and flagellin are essential for Legionella pneumophila-induced cytokine expression. 1860 45

Set2-mediated H3 K36 methylation is an important histone modification on chromatin during transcription elongation. Although Set2 associates with the phosphorylated C-terminal domain (CTD) of RNA polymerase II (RNAPII), the mechanism of Set2 binding to chromatin and subsequent exertion of its methyltransferase activity is relatively uncharacterized. We identified a critical lysine residue in histone H4 that is needed for interaction with Set2 and proper H3 K36 di- and trimethylation. We also determined that the N terminus of Set2 contains a histone H4 interaction motif that allows Set2 to bind histone H4 and nucleosomes. A Set2 mutant lacking the histone H4 interaction motif is able to bind to the phosphorylated CTD of RNAPII and associate with gene-specific loci but is defective for H3 K36 di- and trimethylation. In addition, this Set2 mutant shows increased H4 acetylation and resistance to 6-Azauracil. Overall, our study defines a new interaction between Set2 and histone H4 that mediates trans-histone regulation of H3 K36 methylation, which is needed for the preventative maintenance and integrity of the genome.
...
PMID:Histone H3 K36 methylation is mediated by a trans-histone methylation pathway involving an interaction between Set2 and histone H4. 1892 77

In the present study, we demonstrate that elevated levels of the progesterone receptor (PR)-B isoform in breast cancer cells induces down-regulation of estrogen receptor (ER) alpha mRNA and protein content, causing concomitant repression of the estrogen-regulated genes insulin receptor substrate 1, cyclin D1, and pS2, addressing a specific effect of PR/PR-B on ERalpha gene transcription. ERalpha gene promoter activity was drastically inhibited by PR-B overexpression. Promoter analysis revealed a transcriptionally responsive region containing a half-progesterone response element (PRE) site located at -1757 bp to -1752 bp. Mutation of the half-PRE down-regulated the effect induced by PR/PR-B overexpression. Moreover chromatin immunoprecipitation analyses revealed an increase of PR bound to the ERalpha-regulatory region encompassing the half-PRE site, and the recruitment of a corepressor complex containing nuclear receptor corepressor (NCoR) but not silencing mediator of retinoid and thyroid hormone receptor and DAX1, concomitantly with hypoacetylation of histone H4 and displacement of RNA polymerase II. Furthermore, NCoR ablation studies demonstrated the crucial involvement of NCoR in the down-regulatory effects due to PR-B overexpression on ERalpha protein and mRNA. We also demonstrated that the ERalpha regulation observed in MCF-7 cells depended on PR-B expression because PR-B knockdown partially abrogates the feedback inhibition of ERalpha levels after estrogenic stimulus. Our study provides evidence for a mechanism by which overexpressed PR-B is able to actively repress ERalpha gene expression.
...
PMID:Progesterone receptor B recruits a repressor complex to a half-PRE site of the estrogen receptor alpha gene promoter. 1914 2

An endoparasitoid wasp, Cotesia plutellae, possesses a symbiotic bracovirus (CpBV), which facilitates parasitism of a specific host, such as larvae of the diamondback moth, Plutella xylostella. A viral histone H4 (CpBV-H4) has been found in the CpBV genome and its gene product plays a role in impairing the host insect cellular immune response. Based on its high similarity to histone H4 of P. xylostella apart from its extended N-terminal tail, it has been suspected to alter host gene expression. Histone subunits were purified from parasitized P. xylostella larvae and found to contain both host and viral H4s, confirming a previous report of a possible epigenetic mode of action. Moreover, this study showed that the host H4 levels in the parasitized larvae clearly decreased during the parasitization period, whereas CpBV-H4 levels maintained a significant level without significant changes. To understand the decrease of host H4 levels, transcription levels of host H4 were monitored by quantitative reverse-transcriptase PCR (RT-PCR) and showed a significant decrease in parasitized P. xylostella larvae, whereas no significant change of the mRNA level was detected in nonparasitized larvae. This transcriptional control of host H4 expression was also observed by inducing transient expression of CpBV-H4 in nonparasitized P. xylostella. Moreover, co-injection of CpBV-H4 and its specific double-stranded RNA recovered the host H4 expression level. To identify a functional domain of CpBV-H4 involved in the transcriptional control, the extended N-terminal tail of CpBV-H4 was removed by preparing a truncated viral H4 construct in an expression vector by deleting the N-terminal tail of 38 amino acid residues and inducing its expression in nonparasitized P. xylostella larvae. The truncated CpBV-H4 clearly lost its inhibitory effects on host H4 transcription. Moreover, the presence of CpBV-H4 affects the spreading of host haemocytes by an epigenetic effect, which is at least partly restored in larvae expressing the truncated version of CpBV-H4. This study suggests that the viral H4 encoded in CpBV can alter host gene expression with its extended N-terminal tail.
...
PMID:N-terminal tail of a viral histone H4 encoded in Cotesia plutellae bracovirus is essential to suppress gene expression of host histone H4. 1919 51

The regulation of expression of gluconeogenic genes including glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the liver plays an important role in glucose homeostasis, because aberrant expression of these genes contributes to the development of type 2 diabetes. Previous reports demonstrate that signal transducer and activator of transcription 3 (STAT3) plays a key role in regulating gluconeogenic gene expression, but the mechanism remains unclear. Herein we demonstrate that phosphorylated STAT3 is required for repression of G6Pase expression by IL-6 in both HepG2 cells and mouse liver. Interestingly, PEPCK expression is regulated by STAT3 independent of IL-6 activation. Using in vivo chromatin immunoprecipitation, we demonstrate that STAT3 binds to the promoters of the G6Pase, PEPCK, and suppressor of cytokine signaling (SOCS)3 genes, and its recruitment increases at the G6Pase and SOCS3 promoters with IL-6 treatment. Whereas persistent recruitment of RNA polymerase II is seen on the SOCS3 promoter, consistent with its induction by IL-6, a decrease in polymerase II recruitment and histone H4 acetylation is seen at the G6Pase promoter with IL-6 treatment. Thus STAT3 mediates negative regulation of hepatic gluconeogenic gene expression in vivo by interacting with regulatory regions of these genes.
...
PMID:STAT3 targets the regulatory regions of gluconeogenic genes in vivo. 1926 44

Histones of trypanosomes are quite divergent when compared to histones of most eukaryotes. Nevertheless, the histone H4 of Trypanosoma cruzi, the protozoan that causes Chagas' disease, is acetylated in the N terminus at lysines 4, 10, and 14. Here, we investigated the cellular distribution of histone H4 containing each one of these posttranslational modifications by using specific antibodies. Histone H4 acetylated at lysine 4 (H4-K4ac) is found in the entire nuclear space preferentially at dense chromatin regions, excluding the nucleolus of replicating epimastigote forms of the parasite. In contrast, histone H4 acetylated either at K10 or K14 is found at dispersed foci all over the nuclei and at the interface between dense and nondense chromatin areas as observed by ultrastructural immunocytochemistry. The level of acetylation at K4 decreases in nonreplicating forms of the parasites when compared to K10 and K14 acetylations. Antibodies recognizing the K14 acetylation strongly labeled cells at G2 and M stages of the cell cycle. Besides that, hydroxyurea synchronized parasites show an increased acetylation at K4, K10, and K14 after S phase. Moreover, we do not observed specific colocalization of K4 modifications with the major sites of RNA polymerase II. Upon gamma-irradiation that stops parasite replication until the DNA is repaired, dense chromatin disappears and K4 acetylation decreases, while K10 and K14 acetylation increase. These results indicate that each lysine acetylation has a different role in T. cruzi. While K4 acetylation occurs preferentially in proliferating situations and accumulates in packed chromatin, K10 and K14 acetylations have a particular distribution probably at the boundaries between packed and unpacked chromatin.
...
PMID:Distinct acetylation of Trypanosoma cruzi histone H4 during cell cycle, parasite differentiation, and after DNA damage. 1939 54


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---