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)

Both indirect (transcription-induced stress) and direct effects of polymerase elongation on histone-DNA interactions were studied on closed circular DNA that was either moderately or positively coiled. The templates were reconstituted with (3)H-labeled H2A, H2B, H3, and H4 to form nucleosomes, and transcription was done with T7 RNA polymerase in the presence of a negatively coiled competitor DNA (reconstituted with unlabeled H3 and H4). The first of the two labeled H2A-H2B dimers readily displaced from the highly positively coiled template to the competitor even in the absence of transcription, while the indirect effect of transcription-induced stress was required for the moderately coiled template. The second labeled H2A-H2B dimer required transcription-induced stress for both moderately and highly positively coiled DNA. The displacement of the labeled H3-H4 tetramer also occurred, provided it was associated with an H2A-H2B dimer and a moderately positively coiled DNA. This displacement occurred independent of transcription-induced stress and is likely due to the direct effect of polymerase disruption of histone-DNA interactions. The inclusion of the histone chaperone, NAP1, greatly enhanced the release of both of the two H2A-H2B dimers. These observations are consistent with in vivo observations which indicate that during transcription H2A and H2B are significantly more mobile than H3 and H4 and indicate that transcription-induced positive stress is a likely cause for this selective movement.
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PMID:Histone release during transcription: displacement of the two H2A-H2B dimers in the nucleosome is dependent on different levels of transcription-induced positive stress. 1580 29

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

A high level of the post-translational modification, acetylation, is found on the N-terminal regions of the core histones H2A, H2B, H3, and H4 and is primarily located in the nucleosomes of active genes. An in vitro transcription system was applied, which utilizes T7 RNA polymerase and template DNAs that are either moderately or highly positively coiled, to determine whether acetylation alters the dynamics of histone displacement from these templates during transcription. To measure displacement, an excess of a competitor (negatively coiled DNA reconstituted with unlabeled H3-H4) was included during the transcription process. Acetylated but not unacetylated (3)H-labeled H3-H4 was found to displace with high frequency from the moderately positively coiled template. This displacement of acetylated H3-H4 was not observed when the template was highly positively coiled. Acetylated (3)H-labeled H2A-H2B also preferentially displaced to the competitor, but in this instance, transcription-induced stress on the highly positively coiled template was required. The histone chaperone, NAP1, was found to facilitate the displacement of both H3-H4 and H2A-H2B. Surprisingly, when acetylated H2A-H2B and acetylated H3-H4 were reconstituted together in the same nucleosomes, the displacement of acetylated H2A-H2B was much reduced during transcription. We conclude that acetylation alters nucleosome stability by enhancing displacement of H3-H4, while decreasing the displacement of H2A-H2B. These results are discussed with regard to potential in vivo conditions in which these observations may be relevant.
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PMID:Histone release during transcription: acetylation stabilizes the interaction of the H2A-H2B dimer with the H3-H4 tetramer in nucleosomes that are on highly positively coiled DNA. 1633 96

Crystals of native histone octamers (H2A-H2B)-(H4-H3)-(H3'-H4')-(H2B'-H2A') from chick erythrocytes in 2 M KCl, 1.35 M potassium phosphate pH 6.9 diffract X-rays to 1.90 A resolution, yielding a structure with an R(work) value of 18.7% and an Rfree of 22.2%. The crystal space group is P6(5), the asymmetric unit of which contains one complete octamer. This high-resolution model of the histone-core octamer allows further insight into intermolecular interactions, including water molecules, that dock the histone dimers to the tetramer in the nucleosome-core particle and have relevance to nucleosome remodelling. The three key areas analysed are the H2A'-H3-H4 molecular cluster (also H2A-H3'-H4'), the H4-H2B' interaction (also H4'-H2B) and the H2A'-H4 beta-sheet interaction (also H2A-H4'). The latter of these three regions is important to nucleosome remodelling by RNA polymerase II, as it is shown to be a likely core-histone binding site, and its disruption creates an instability in the nucleosome-core particle. A majority of the water molecules in the high-resolution octamer have positions that correlate to similar positions in the high-resolution nucleosome-core particle structure, suggesting that the high-resolution octamer model can be used for comparative studies with the high-resolution nucleosome-core particle.
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PMID:High-resolution structure of the native histone octamer. 1651 Oct 91

The factors required for the delivery of RNA polymerase II to class II promoters using naked DNA were all identified by 1998, yet their exact mechanisms of action were not fully understood in all cases, and in some instances, their precise function still remains unknown. Nonetheless, a complete understanding of the complexity of the RNA polymerase II transcription cycle necessitated the development of assays that include chromatinized DNA templates. At this time, the field was actively searching for factors that allow transcription initiation on chromatinized templates. We began studies using chromatin templates in an attempt to identify factor(s) that permit RNA polymerase II to traverse nucleosomes, i.e. that allow elongation on chromatinized DNA templates. The challenge herein was to develop an assay that directly measured the ability of transcriptionally engaged RNA polymerase II to traverse nucleosomes. This approach resulted in the isolation of FACT, a heterodimer in humans comprised of Spt16 and SSRP1. Defined functional biochemical assays corroborated genetic studies in yeast that allowed the elucidation of FACT function in vivo. Collectively, these approaches demonstrate that FACT is a factor that allows RNA polymerase II to traverse nucleosomes in vitro and in vivo by removing one H2A/H2B dimer. More recent studies using a fully defined chromatin reconstitution/transcription assay revealed that FACT activity is greatly stimulated by post-translational modification of the histone polypeptides, specifically by monoubiquitination of lysine 120 of human histone H2B.
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PMID:de FACTo nucleosome dynamics. 1676 22

Eukaryotic genes are controlled by sequence-specific DNA-binding proteins, chromatin regulators, general transcription factors, and elongation factors. Here we examine the genome-wide location of representative members of these groups and their redistribution when the Saccharomyces cerevisiae genome is reprogrammed by heat shock. As expected, assembly of active transcription complexes is coupled to eviction of H2A.Z nucleosomes, and disassembly is coupled to the return of nucleosomes. Remarkably, a large number of promoters assemble into partial preinitiation complexes (partial PICs), containing TFIIA, TFIID (and/or SAGA), TFIIB, TFIIE, and TFIIF. However, RNA polymerase II and TFIIH are generally not recruited, and nucleosomes are not displaced. These promoters may be preparing for additional stress that naturally accompany heat stress. For example, we find that oxidative stress, which often occurs with prolonged exposure of cells to high temperature, converts partial PICs into full PICs. Partial PICs therefore represent novel regulated intermediates that assemble at promoters in the midst of chromatin.
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PMID:Full and partial genome-wide assembly and disassembly of the yeast transcription machinery in response to heat shock. 1691 75

Nucleosomes uniquely positioned on high-affinity DNA sequences present a polar barrier to transcription by human and yeast RNA polymerase II (Pol II). In one transcriptional orientation, these nucleosomes provide a strong, factor- and salt-insensitive barrier at the entry into the H3/H4 tetramer that can be recapitulated without H2A/H2B dimers. The same nucleosomes transcribed in the opposite orientation form a weaker, more diffuse barrier that is largely relieved by higher salt, TFIIS, or FACT. Barrier properties are therefore dictated by both the local nucleosome structure (influenced by the strength of the histone-DNA interactions) and the location of the high-affinity DNA region within the nucleosome. Pol II transcribes DNA sequences at the entry into the tetramer much less efficiently than the same sequences located distal to the nucleosome dyad. Thus, entry into the tetramer by Pol II facilitates further transcription, perhaps due to partial unfolding of the tetramer from DNA.
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PMID:Nucleosomes can form a polar barrier to transcript elongation by RNA polymerase II. 1708 95

Transcription from the mouse mammary tumor virus (MMTV) promoter can be induced by glucocorticoids or progestins. Progesterone treatment of cultured cells carrying an integrated single copy of an MMTV transgene leads to recruitment of progesterone receptor (PR), SWI/SNF, and SNF2h-related complexes to MMTV promoter. Recruitment is accompanied by selective displacement of histones H2A and H2B from the nucleosome B. In nucleosomes assembled on promoter sequences, SWI/SNF displaces histones H2A and H2B from MMTV nucleosome B, but not from other MMTV nucleosomes or from an rDNA promoter nucleosome. Thus, the outcome of nucleosome remodeling by purified SWI/SNF depends on the DNA sequence. On the other hand, 5 min after hormone treatment, the cytoplasmic signaling cascade Src/Ras/Erk is activated via an interaction of PR with the estrogen receptor, which activates Src. As a consequence of Erk activation PR is phosphorylated, Msk1 is activated, and a ternary complex PR-Erk-Msk1 is recruited to MMTV nucleosome B. Msk1 phosphorylates H3 at serine 10, which is followed by acetylation at lysine 14, displacement of HP1gamma, and recruitment of Brg1, PCAF, and RNA polymerase II. Blocking Erk activation or Msk1 activity prevents induction of the MMTV transgene. Thus, the rapid nongenomic effects of progestins are essential for their transcriptional effects on certain progestin target genes. In rat endometrial stromal cells, picomolar concentrations of progestins trigger the cross talk of PR with ERbeta that activates the Erk and Akt kinase pathways leading to cell proliferation in the absence of direct transcriptional effects of the ligand-activated PR. Thus, depending on the cellular context rapid kinase activation and transcriptional effect play different roles in the physiological response to progestins.
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PMID:Chromatin remodeling and control of cell proliferation by progestins via cross talk of progesterone receptor with the estrogen receptors and kinase signaling pathways. 1726 55

The process of transcript elongation by RNA polymerase II (Pol II) involves transcription-dependent exchange and displacement of all core histones and is tightly controlled by numerous protein complexes modifying chromatin structure. These processes can contribute to regulation of transcription initiation and elongation, as well as the chromatin state. Recent data suggest that the histone octamer is displaced from DNA at a high rate of transcription, but can survive less frequent transcription that is accompanied only by partial loss of H2A/H2B histones. Here we propose that critical density of Pol II molecules could be required for displacement of the histone octamer and discuss mechanisms that are most likely involved in the processes of histone exchange.
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PMID:Transcription through chromatin by RNA polymerase II: histone displacement and exchange. 1731 61

Histone modifications are implicated in influencing gene expression. We have generated high-resolution maps for the genome-wide distribution of 20 histone lysine and arginine methylations as well as histone variant H2A.Z, RNA polymerase II, and the insulator binding protein CTCF across the human genome using the Solexa 1G sequencing technology. Typical patterns of histone methylations exhibited at promoters, insulators, enhancers, and transcribed regions are identified. The monomethylations of H3K27, H3K9, H4K20, H3K79, and H2BK5 are all linked to gene activation, whereas trimethylations of H3K27, H3K9, and H3K79 are linked to repression. H2A.Z associates with functional regulatory elements, and CTCF marks boundaries of histone methylation domains. Chromosome banding patterns are correlated with unique patterns of histone modifications. Chromosome breakpoints detected in T cell cancers frequently reside in chromatin regions associated with H3K4 methylations. Our data provide new insights into the function of histone methylation and chromatin organization in genome function.
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PMID:High-resolution profiling of histone methylations in the human genome. 1804 24


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