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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)

The post-translational modification of histones and the incorporation of core histone variants play key roles in governing gene expression. Many eukaryotic genes regulate their expression by limiting the escape of RNA polymerase from promoter-proximal pause sites. Here we report that elongating RNA polymerase II complexes encounter distinct chromatin landscapes that are marked by methylation of lysine residues Lys(4), Lys(79), and Lys(36) of histone H3. However, neither histone methylation nor acetylation directly regulates the release of elongation complexes stalled at promoter-proximal pause sites of the c-myc gene. In contrast, transcriptional activation is associated with local displacement of the histone variant H2A.Z within the transcribed region and incorporation of the major histone variant H2A. This result indicates that transcribing RNA polymerase II remodels chromatin in part through coincident displacement of H2A.Z-H2B dimers and incorporation of H2A-H2B dimers. In combination, these results suggest a new model in which the incorporation of H2A.Z into nucleosomes down-regulates transcription; at the same time it may act as a cellular memory for transcriptionally poised gene domains.
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PMID:Transcription-induced chromatin remodeling at the c-myc gene involves the local exchange of histone H2A.Z. 1587 76

T-cells retain cell-type-specific programming for IL-2 inducibility through many rounds of division without being stimulated to transcribe the locus. To understand the layering of controls needed to poise this gene heritably for activation, we have used chromatin immunoprecipitation to map histone modifications across the murine IL2 locus, from -10.2 through +0.25 kb, in induction-competent and incompetent cells. In highly inducible EL4 T-lineage cells, stimulation with PMA/A23187 induced strong acetylation of histone H3 and H4, in parallel with transcriptional activation, from -4.6 through +0.25 kb. However, dimethylation of histone H3/K4 was already fully elevated across the same restricted domain before stimulation, with little change after stimulation. RNA polymerase II binding, in contrast, was only found at the known promoter region after stimulation. Similar patterns of histone modifications were seen also in normal IL-2-inducible T-lineage cells. However, neither acetylated histone H3, H4 nor dimethylated histone H3/K4 marking was detected, with or without stimulation, in expression-incompetent cells (NIH/3T3 or Scid.adh). These results identify a discrete new domain of IL2 regulatory sequence marked by dimethylated histone H3/K4 in expression-permissive T-cells even when they are not transcribing IL2, setting boundaries for histone H3 and H4 acetylation when the IL2 gene is transcriptionally activated.
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PMID:Cell-type-specific epigenetic marking of the IL2 gene at a distal cis-regulatory region in competent, nontranscribing T-cells. 1593 96

The mixed-lineage leukemia (MLL1/ALL-1/HRX) histone methyltransferase is involved in the epigenetic maintenance of transcriptional memory and the pathogenesis of human leukemias. To understand its role in cell type specification, we determined the human genomic binding sites of MLL1. We found that MLL1 functions as a human equivalent of yeast Set1. Like Set1, MLL1 localizes with RNA polymerase II (Pol II) to the 5' end of actively transcribed genes, where histone H3 lysine 4 trimethylation occurs. Consistent with this global role in transcription, MLL1 also localizes to microRNA (miRNA) loci that are involved in leukemia and hematopoiesis. In contrast to the 5' proximal binding behavior at most protein-coding genes, MLL1 occupies an extensive domain within a transcriptionally active region of the HoxA cluster. The ability of MLL1 to serve as a start site-specific global transcriptional regulator and to participate in larger chromatin domains at the Hox genes reveals dual roles for MLL1 in maintenance of cellular identity.
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PMID:Global and Hox-specific roles for the MLL1 methyltransferase. 1594 28

Covalent modifications to histones are key epigenetic marks that control gene transcription. Multiple lysine residues on histone H3 are methylated (me), but their functions are unclear. Here, we demonstrate two phases of combinatorial and dynamic H3 methylation during induction of transcription at MET16 in yeast. K4me3 with K36me2/3 define a postinitiation regulatory phase and precede the appearance of K4me2 with K79me2 at the onset of transcript elongation. The Isw1 ATPase delays the release of initiated RNA polymerase II (RNAPII) into elongation to facilitate chromatin modifications. The Spp1 subunit of complex associated with Set1 (COMPASS) and Set2, determining K4me3 and K36me2/3, respectively, are required for transient NuA4-dependent H4K8ac. This releases RNAPII from Isw1 control and promotes controlled transcription elongation and termination. We propose that newly initiated RNAPII is under epigenetic control.
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PMID:Dynamic lysine methylation on histone H3 defines the regulatory phase of gene transcription. 1594 46

Using chromatin immunoprecipitation assays, we studied the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated recruitment of the aryl hydrocarbon receptor (AhR) and several co-regulators to the CYP1A1 promoter. AhR displayed a time-dependent recruitment, reaching a peak at 75 min and maintaining promoter occupancy for the remainder of the time course. Recruitment of AhR was followed by TIF2/SRC2, which preceded CBP, histone H3 acetylation, and RNA polymerase II (RNAPII). Simultaneous recruitment to the enhancer and the TATA box region suggests the formation of a large multiprotein complex bridging the two promoter regions. Interestingly, estrogen receptor alpha (ERalpha) displayed a TCDD- and time-dependent recruitment to the CYP1A1 promoter, which was increased by co-treatment with estradiol. Transfection in HuH7 human liver cells confirmed previously reported ERalpha enhancement of AhR activity. In contrast, TCDD did not induce the recruitment of ERalpha to the estrogen-responsive pS2 promoter, and after 120 min of co-treatment with estradiol, ERalpha is still present on the CYP1A1 promoter but no longer at pS2. RNA interference studies with T47D cells support a role for ERalpha in TCDD-dependent CYP1A1 expression. Our data suggest that ERalpha acts as a coregulator of AhR-mediated transcriptional activation and that the recruitment of ERalpha by AhR represents a novel mechanism AhR-ERalpha cross talk.
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PMID:Aryl hydrocarbon receptor-mediated transcription: ligand-dependent recruitment of estrogen receptor alpha to 2,3,7,8-tetrachlorodibenzo-p-dioxin-responsive promoters. 1596 90

The organization of eukaryotic genomes into distinct structural and functional domains is important for the regulation and transduction of genetic information. Here, we investigated heterochromatin and euchromatin profiles of the entire fission yeast genome and explored the role of RNA interference (RNAi) in genome organization. Histone H3 methylated at Lys4, which defines euchromatin, was not only distributed across most of the chromosomal landscape but was also present at the centromere core, the site of kinetochore assembly. In contrast, histone H3 methylated at Lys9 and its interacting protein Swi6/HP1, which define heterochromatin, coated extended domains associated with a variety of repeat elements and small islands corresponding to meiotic genes. Notably, RNAi components were distributed throughout all these heterochromatin domains, and their localization depended on Clr4/Suv39h histone methyltransferase. Sequencing of small interfering RNAs (siRNAs) associated with the RITS RNAi effector complex identified hot spots of siRNAs, which mapped to a diverse array of elements in these RNAi-heterochromatin domains. We found that Clr4/Suv39h predominantly silenced repeat elements whose derived transcripts, transcribed mainly by RNA polymerase II, serve as a source for siRNAs. Our analyses also uncover an important role for the RNAi machinery in maintaining genomic integrity.
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PMID:Comprehensive analysis of heterochromatin- and RNAi-mediated epigenetic control of the fission yeast genome. 1597 7

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

Methylation of histones modulates chromatin structure and function. Whereas methylation of histone H3 on lysines 4, 36, and 79 has been linked with gene activation, methylation of H3 on lysines 9 and 27 and histone H4 on lysine 20 is associated with heterochromatin and some repressed genes within euchromatin. Here, we show that H3K9 di- and trimethylation occur in the transcribed region of active genes in mammalian chromatin. This modification is dynamic, as it increases during activation of transcription and is rapidly removed upon gene repression. Heterochromatin Protein 1gamma (HP1gamma), a protein containing a chromo-domain that recognizes H3K9 methylation, is also present in the transcribed region of all active genes examined. Both the presence of HP1gamma and H3K9 methylation are dependent upon elongation by RNA polymerase II. These findings demonstrate novel roles for H3K9 methylation and HP1gamma in transcription activation.
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PMID:Histone H3 lysine 9 methylation and HP1gamma are associated with transcription elongation through mammalian chromatin. 1606 Nov 84

Set2 methylation of histone H3 at lysine 36 (K36) has recently been shown to be associated with RNA polymerase II (Pol II) elongation in Saccharomyces cerevisiae. However, whether this modification is conserved and associated with transcription elongation in other organisms is not known. Here we report the identification and characterization of the Set2 ortholog responsible for K36 methylation in the fission yeast Schizosaccharomyces pombe. We find that similar to the budding yeast enzyme, S. pombe Set2 is also a robust nucleosome-selective H3 methyltransferase that is specific for K36. Deletion of the S. pombe set2+ gene results in complete abolishment of K36 methylation as well as a slow-growth phenotype on plates containing synthetic medium. These results indicate that Set2 is the sole enzyme responsible for this modification in fission yeast and is important for cell growth under stressed conditions. Using the chromatin immunoprecipitation assay, we demonstrate that K36 methylation in S. pombe is associated with the transcribed regions of Pol II-regulated genes and is devoid in regions that are not transcribed by Pol II. Consistent with a role for Set2 in transcription elongation, we find that S. pombe Set2 associates with the hyperphosphorylated form of Pol II and can fully rescue K36 methylation and Pol II interaction in budding yeast cells deleted for Set2. These results, along with our finding that K36 methylation is highly conserved among eukaryotes, imply a conserved role for this modification in the transcription elongation process.
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PMID:Histone H3 K36 methylation is associated with transcription elongation in Schizosaccharomyces pombe. 1608 49

Parafibromin is a putative tumor suppressor encoded by HRPT2, mutations in which have been implicated in the familial tumor syndrome hyperparathyroidism jaw tumor syndrome (HPT-JT), and sporadic parathyroid carcinoma. Recently, parafibromin has been shown to be an accessory factor for RNA polymerase II as part of the human Paf 1 complex, suggesting, as has been shown for its yeast homologue (Cdc 73), that it may have a role as an important regulator of transcription. Parafibromin has also been shown to interact with a histone methyltransferase complex that methylates histone H3 and to inhibit proliferation when overexpressed in mammalian cell lines. Despite these findings, the cellular localization of parafibromin has been controversial, with reports of both nuclear and nucleocytoplasmic localization. We have expressed wild-type and mutant parafibromin tagged with enhanced green fluorescent protein and have identified a functional bipartite nuclear localization signal (NLS) at residues 125-139 (nucleotides 373-417), KRAADEVLAEAKKPR, that is evolutionarily conserved and critical for the nuclear localization of parafibromin. We have also shown that the C-terminal arm of this bipartite NLS plays the primary role in nuclear localization. In support of these findings, specific HRPT2 mutations identified in HPT-JT or sporadic parathyroid carcinoma predicted to truncate parafibromin upstream of or within this NLS disrupt nuclear localization.
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PMID:Identification of a functional bipartite nuclear localization signal in the tumor suppressor parafibromin. 1611 86


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