Coupling polymerase pausing and chromatin landscapes for precise regulation of transcription
ABSTRACT Altering gene expression in response to stimuli is a pivotal mechanism through which organisms execute developmental programs and respond to changes in their environment. Packaging of promoter DNA into chromatin can greatly impact the ability of RNA polymerase II to access and transcribe a gene. Promoter chromatin environments thus play a central role in establishing transcriptional output appropriate for specific environmental conditions or developmental states. Recent genomic studies have illuminated general principles of chromatin organization and deepened our understanding of how promoter sequence and nucleosome architecture may impact gene expression. Concurrently, pausing of polymerase during early elongation has been recognized as an important event influencing transcription of genes within stimulus-responsive networks. Promoters regulated by pausing are now recognized to possess a distinct chromatin architecture that may facilitate the plasticity of gene expression in response to signaling events. Here we review advances in understanding chromatin and pausing, and explore how coupling Pol II pausing to distinct promoter architectures may help organisms achieve flexible yet precise transcriptional control. This article is part of a Special Issue entitled: Chromatin in time and space.
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- "In addition, cells pre-treated with either inhibitor revealed a striking increase in the −1 IL1B nucleosome, an additional distinction from TNF. The presence of uniquely phased −1 nucleosomes in promoter NDR has been suggested to inhibit Pol II recruitment , , but to our knowledge this is the first report indicating its role affecting inducible IE activation in human immune cells and may reflect loss of an important priming function for this gene. The IL1B and TNF nucleosomes in HEK293 exhibited higher levels, especially for the −1 nucleosome. "
ABSTRACT: Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPβ and NF-κB. Activation and DNA binding of these two pre-expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P-TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators.PLoS ONE 08/2013; 8(8):e70622. DOI:10.1371/journal.pone.0070622 · 3.23 Impact Factor
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- "The INO80 complex has been implicated in PcG repression of HOX genes in Drosophila . Promoter proximal pausing of RNAP II is linked to a distinctive pattern of nucleosome arrangement around the TSS , , . GAF has been shown to cooperate with NURF to remodel nucleosomes and increase DNA accessibility at the paused Hsp70 promoter . "
ABSTRACT: The early elongation checkpoint regulated by Positive Transcription Elongation Factor b (P-TEFb) is a critical control point for the expression of many genes. Spt5 interacts directly with RNA polymerase II and has an essential role in establishing this checkpoint, and also for further transcript elongation. Here we demonstrate that Drosophila Spt5 interacts both physically and genetically with the Polycomb Group (PcG) protein Pleiohomeotic (Pho), and the majority of Pho binding sites overlap with Spt5 binding sites across the genome in S2 cells. Our results indicate that Pho can interact with Spt5 to regulate transcription elongation in a gene specific manner.PLoS ONE 07/2013; 8(7):e70184. DOI:10.1371/journal.pone.0070184 · 3.23 Impact Factor
Article: Gdown1[Show abstract] [Hide abstract]
ABSTRACT: Gdown1 is a substoichiometric RNA polymerase II subunit that modulates effects of both Mediator and elongation factors in vitro and is broadly distributed across the human genome. Here we assemble the existing information on Gdown1, provide additional bioinformatics analyses, and propose a working model for Gdown1 function.Transcription 07/2012; 3(4). DOI:10.4161/trns.20600