Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-coding (nc)RNAs are key players in numerous biological processes such as gene regulation, chromatin domain formation and genome stability. Large ncRNAs interact with histone modifiers and are involved in cancer development, X-chromosome inactivation and autosomal gene imprinting. However, despite recent evidence showing that pervasive transcription is more widespread than previously thought, only a few examples mediating gene regulation in eukaryotes have been described. In Saccharomyces cerevisiae, the bona-fide regulatory ncRNAs are destabilized by the Xrn1 5'-3' RNA exonuclease (also known as Kem1), but the genome-wide characterization of the entire regulatory ncRNA family remains elusive. Here, using strand-specific RNA sequencing (RNA-seq), we identify a novel class of 1,658 Xrn1-sensitive unstable transcripts (XUTs) in which 66% are antisense to open reading frames. These transcripts are polyadenylated and RNA polymerase II (RNAPII)-dependent. The majority of XUTs strongly accumulate in lithium-containing media, indicating that they might have a role in adaptive responses to changes in growth conditions. Notably, RNAPII chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) analysis of Xrn1-deficient strains revealed a significant decrease of RNAPII occupancy over 273 genes with antisense XUTs. These genes show an unusual bias for H3K4me3 marks and require the Set1 histone H3 lysine 4 methyl-transferase for silencing. Furthermore, abolishing H3K4me3 triggers the silencing of other genes with antisense XUTs, supporting a model in which H3K4me3 antagonizes antisense ncRNA repressive activity. Our results demonstrate that antisense ncRNA-mediated regulation is a general regulatory pathway for gene expression in S. cerevisiae.
 ...
PMID:XUTs are a class of Xrn1-sensitive antisense regulatory non-coding RNA in yeast. 2169 27

In Saccharomyces cerevisiae, the Nrd1-Nab3-Sen1 pathway mediates the termination of snoRNAs and cryptic unstable transcripts (CUTs). Both Nrd1 and the Set1 histone H3K4 methyltransferase complex interact with RNA polymerase II (Pol II) during early elongation, leading us to test whether these two processes are functionally linked. The deletion of SET1 exacerbates the growth rate and termination defects of nrd1 mutants. Set1 is important for the appropriate recruitment of Nrd1. Additionally, Set1 modulates histone acetylation levels in the promoter-proximal region via the Rpd3L deacetylase and NuA3 acetyltransferase complexes, both of which contain PHD finger proteins that bind methylated H3K4. Increased levels of histone acetylation reduce the efficiency of Nrd1-dependent termination. We speculate that Set1 promotes proper early termination by the Nrd1-Nab3-Sen1 complex by affecting the kinetics of Pol II transcription in early elongation.
 ...
PMID:H3K4 trimethylation by Set1 promotes efficient termination by the Nrd1-Nab3-Sen1 pathway. 2170 22

A nucleosome is composed of intrinsically disordered histone tails and a structured nucleosome core surrounded by DNA. A variety of modifiable residues on the intrinsically disordered histone tails have been identified in the last decade. Mapping of the functional residues on the structured nucleosome core surface was recently initiated by global analysis of a comprehensive histone point mutant library (histone-GLibrary). It stands to reason that a functional relationship exists between modifiable residues on the intrinsically disordered histone tails and functional residues on the structured nucleosome core; however, this matter has been poorly explored. During transcription elongation, trimethylation of histone H3 at lysine 36 (H3-K36me3) is mediated by histone methyltransferase Set2, which binds to RNA polymerase II. Here, we used a histone-GLibrary that encompasses the nucleosomal DNA entry/exit site to show that six residues (H2A-G107, H2A-I112, H2A-L117, H3-T45, H3-R49 and H3-R52) form a surface on the structured nucleosome core and regulate H3-K36me3. Trimethylation at H3-K4 introduced by histone methyltransferase Set1 was not affected by the mutation of any of the six residues. Chromatin immunoprecipitation analysis showed that most of these residues are critical for the chromatin association of RNA polymerase II and Set2, suggesting that these components regulate H3-K36me3 through functional interactions with the structured nucleosome core surface.
 ...
PMID:Nucleosome surface containing nucleosomal DNA entry/exit site regulates H3-K36me3 via association with RNA polymerase II and Set2. 2221 75

Transcript elongation by RNA polymerase II (RNAPII) is accompanied by conserved patterns of histone modification. Whereas histone modifications have established roles in transcription initiation, their functions during elongation are not understood. Mono-ubiquitylation of histone H2B (H2Bub1) plays a key role in coordinating co-transcriptional histone modification by promoting site-specific methylation of histone H3. H2Bub1 also regulates gene expression through an unidentified, methylation-independent mechanism. Here we reveal bidirectional communication between H2Bub1 and Cdk9, the ortholog of metazoan positive transcription elongation factor b (P-TEFb), in the fission yeast Schizosaccharomyces pombe. Chemical and classical genetic analyses indicate that lowering Cdk9 activity or preventing phosphorylation of its substrate, the transcription processivity factor Spt5, reduces H2Bub1 in vivo. Conversely, mutations in the H2Bub1 pathway impair Cdk9 recruitment to chromatin and decrease Spt5 phosphorylation. Moreover, an Spt5 phosphorylation-site mutation, combined with deletion of the histone H3 Lys4 methyltransferase Set1, phenocopies morphologic and growth defects due to H2Bub1 loss, suggesting independent, partially redundant roles for Cdk9 and Set1 downstream of H2Bub1. Surprisingly, mutation of the histone H2B ubiquitin-acceptor residue relaxes the Cdk9 activity requirement in vivo, and cdk9 mutations suppress cell-morphology defects in H2Bub1-deficient strains. Genome-wide analyses by chromatin immunoprecipitation also demonstrate opposing effects of Cdk9 and H2Bub1 on distribution of transcribing RNAPII. Therefore, whereas mutual dependence of H2Bub1 and Spt5 phosphorylation indicates positive feedback, mutual suppression by cdk9 and H2Bub1-pathway mutations suggests antagonistic functions that must be kept in balance to regulate elongation. Loss of H2Bub1 disrupts that balance and leads to deranged gene expression and aberrant cell morphologies, revealing a novel function of a conserved, co-transcriptional histone modification.
 ...
PMID:A positive feedback loop links opposing functions of P-TEFb/Cdk9 and histone H2B ubiquitylation to regulate transcript elongation in fission yeast. 2287 98

The ubiquitin-like SUMO system regulates gene expression, but the molecular insights into this process are incomplete. We show that the SUMO-specific isopeptidase SENP3 controls H3K4 methylation by regulating histone-modifying SET1/MLL complexes. SET1/MLL complexes are composed of a histone methyltransferase and the regulatory components WDR5, RbBP5, Ash2L, and DPY-30. MLL1/MLL2 complexes contain menin as additional component and are particularly important for the activation of HOX genes. We demonstrate that SENP3 is associated with MLL1/MLL2 complexes and catalyzes deSUMOylation of RbBP5. This is required for activation of a subset of HOX genes, including the developmental regulator DLX3. In the absence of SENP3, the association of menin and Ash2L with the DLX3 gene is impaired, leading to decreased H3K4 methylation and reduced recruitment of active RNA polymerase II. Importantly, the SENP3-DLX3 pathway dictates osteogenic differentiation of human stem cells, thus delineating the importance of balanced SUMOylation for epigenetic control of gene expression programs.
...
PMID:The SUMO-specific isopeptidase SENP3 regulates MLL1/MLL2 methyltransferase complexes and controls osteogenic differentiation. 2493 Jul 34

The phosphorylation of the RNA polymerase II C-terminal domain (CTD) plays a key role in delineating transcribed regions within chromatin by recruiting histone methylases and deacetylases. Using genome-wide nucleosome mapping, we show that CTD S2 phosphorylation controls nucleosome dynamics in the promoter of a subset of 324 genes, including the regulators of cell differentiation ste11 and metabolic adaptation inv1. Mechanistic studies on these genes indicate that during gene activation a local increase of phospho-S2 CTD nearby the promoter impairs the phospho-S5 CTD-dependent recruitment of Set1 and the subsequent recruitment of specific HDACs, which leads to nucleosome depletion and efficient transcription. The early increase of phospho-S2 results from the phosphorylation of the CTD S2 kinase Lsk1 by MAP kinase in response to cellular signalling. The artificial tethering of the Lsk1 kinase at the ste11 promoter is sufficient to activate transcription. Therefore, signalling through the CTD code regulates promoter nucleosomes dynamics.
...
PMID:Promoter nucleosome dynamics regulated by signalling through the CTD code. 2609 23

Upon recruitment to active enhancers and promoters, RNA polymerase II (Pol II) generates short non-coding transcripts of unclear function. The mechanisms that control the length and the amount of ncRNAs generated by cis-regulatory elements are largely unknown. Here, we show that the adaptor protein WDR82 and its associated complexes actively limit such non-coding transcription. WDR82 targets the SET1 H3K4 methyltransferases and the nuclear protein phosphatase 1 (PP1) complexes to the initiating Pol II. WDR82 and PP1 also interact with components of the transcriptional termination and RNA processing machineries. Depletion of WDR82, SET1, or the PP1 subunit required for its nuclear import caused distinct but overlapping transcription termination defects at highly expressed genes and active enhancers and promoters, thus enabling the increased synthesis of unusually long ncRNAs. These data indicate that transcription initiated from cis-regulatory elements is tightly coordinated with termination mechanisms that impose the synthesis of short RNAs.
...
PMID:Transcription of Mammalian cis-Regulatory Elements Is Restrained by Actively Enforced Early Termination. 2659 20

Histone modification is a critical determinant of the frequency and location of meiotic double-strand breaks (DSBs), and thus recombination. Set1-dependent histone H3K4 methylation and Dot1-dependent H3K79 methylation play important roles in this process in budding yeast. Given that the RNA polymerase II associated factor 1 complex, Paf1C, promotes both types of methylation, we addressed the role of the Paf1C component, Rtf1, in the regulation of meiotic DSB formation. Similar to a set1 mutation, disruption of RTF1 decreased the occurrence of DSBs in the genome. However, the rtf1 set1 double mutant exhibited a larger reduction in the levels of DSBs than either of the single mutants, indicating independent contributions of Rtf1 and Set1 to DSB formation. Importantly, the distribution of DSBs along chromosomes in the rtf1 mutant changed in a manner that was different from the distributions observed in both set1 and set1 dot1 mutants, including enhanced DSB formation at some DSB-cold regions that are occupied by nucleosomes in wild-type cells. These observations suggest that Rtf1, and by extension the Paf1C, modulate the genomic DSB landscape independently of H3K4 methylation.
...
PMID:The Double-Strand Break Landscape of Meiotic Chromosomes Is Shaped by the Paf1 Transcription Elongation Complex in Saccharomyces cerevisiae. 2662 41

Gene expression during Drosophila development is subject to regulation by the Polycomb (Pc), Trithorax (Trx), and Compass chromatin modifier complexes. O-GlcNAc transferase (OGT/SXC) is essential for Pc repression suggesting that the O-GlcNAcylation of proteins plays a key role in regulating development. OGT transfers O-GlcNAc onto serine and threonine residues in intrinsically disordered domains of key transcriptional regulators; O-GlcNAcase (OGA) removes the modification. To pinpoint genomic regions that are regulated by O-GlcNAc levels, we performed ChIP-chip and microarray analysis after OGT or OGA RNAi knockdown in S2 cells. After OGA RNAi, we observed a genome-wide increase in the intensity of most O-GlcNAc-occupied regions including genes linked to cell cycle, ubiquitin, and steroid response. In contrast, O-GlcNAc levels were strikingly insensitive to OGA RNAi at sites of polycomb repression such as the Hox and NK homeobox gene clusters. Microarray analysis suggested that altered O-GlcNAc cycling perturbed the expression of genes associated with morphogenesis and cell cycle regulation. We then produced a viable null allele of oga (oga(del.1)) in Drosophila allowing visualization of altered O-GlcNAc cycling on polytene chromosomes. We found that trithorax (TRX), absent small or homeotic discs 1 (ASH1), and Compass member SET1 histone methyltransferases were O-GlcNAc-modified in oga(del.1) mutants. The oga(del.1) mutants displayed altered expression of a distinct set of cell cycle-related genes. Our results show that the loss of OGA in Drosophila globally impacts the epigenetic machinery allowing O-GlcNAc accumulation on RNA polymerase II and numerous chromatin factors including TRX, ASH1, and SET1.
...
PMID:Drosophila O-GlcNAcase Deletion Globally Perturbs Chromatin O-GlcNAcylation. 2695 42

In yeast and humans, previous experiences can lead to epigenetic transcriptional memory: repressed genes that exhibit mitotically heritable changes in chromatin structure and promoter recruitment of poised RNA polymerase II preinitiation complex (RNAPII PIC), which enhances future reactivation. Here, we show that INO1 memory in yeast is initiated by binding of the Sfl1 transcription factor to the cis-acting Memory Recruitment Sequence, targeting INO1 to the nuclear periphery. Memory requires a remodeled form of the Set1/COMPASS methyltransferase lacking Spp1, which dimethylates histone H3 lysine 4 (H3K4me2). H3K4me2 recruits the SET3C complex, which plays an essential role in maintaining this mark. Finally, while active INO1 is associated with Cdk8(-) Mediator, during memory, Cdk8(+) Mediator recruits poised RNAPII PIC lacking the Kin28 CTD kinase. Aspects of this mechanism are generalizable to yeast and conserved in human cells. Thus, COMPASS and Mediator are repurposed to promote epigenetic transcriptional poising by a highly conserved mechanism.
 ...
PMID:Set1/COMPASS and Mediator are repurposed to promote epigenetic transcriptional memory. 2733 23


<< Previous 1 2 3 4 5 Next >>