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Gene-specific mechanisms dictate glucocorticoid receptor-mediated repression of inflammatory response genes in macrophages [RNA-seq]

ABSTRACT: The Glucocorticoid Receptor (GR) potently represses macrophage-elicited inflammation, however, the underlying mechanisms remain obscure. Our genome-wide analysis reveals that pro-inflammatory paused genes, activated via global negative elongation factor (NELF) dissociation and RNA Polymerase (Pol)2 release from early elongation arrest, and non-paused genes, induced by de novo Pol2 recruitment, are equally susceptible to acute glucocorticoid repression. Moreover, in both cases the dominant mechanism involves rapid GR tethering to p65 at NF-kB binding sites. Yet, specifically at paused genes, GR activation triggers widespread promoter accumulation of NELF, with myeloid cell-specific NELF deletion conferring glucocorticoid resistance. Conversely, at non-paused genes, GR attenuates the recruitment of p300 and histone acetylation, leading to a failure to assemble BRD4 and Mediator at promoters and enhancers, ultimately blocking Pol2 initiation. Thus, GR displays no preference for a specific pro-inflammatory gene class, however, it effects repression by targeting distinct temporal events and components of transcriptional machinery

ORGANISM(S): Mus musculus

PROVIDER: GSE110243 | GEO | 2018/02/28

REPOSITORIES: GEO

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Gene-specific mechanisms dictate glucocorticoid receptor-mediated repression of inflammatory response genes in macrophages [ChIP-seq]

Project description:The Glucocorticoid Receptor (GR) potently represses macrophage-elicited inflammation, however, the underlying mechanisms remain obscure. Our genome-wide analysis reveals that pro-inflammatory paused genes, activated via global negative elongation factor (NELF) dissociation and RNA Polymerase (Pol)2 release from early elongation arrest, and non-paused genes, induced by de novo Pol2 recruitment, are equally susceptible to acute glucocorticoid repression. Moreover, in both cases the dominant mechanism involves rapid GR tethering to p65 at NF-kB binding sites. Yet, specifically at paused genes, GR activation triggers widespread promoter accumulation of NELF, with myeloid cell-specific NELF deletion conferring glucocorticoid resistance. Conversely, at non-paused genes, GR attenuates the recruitment of p300 and histone acetylation, leading to a failure to assemble BRD4 and Mediator at promoters and enhancers, ultimately blocking Pol2 initiation. Thus, GR displays no preference for a specific pro-inflammatory gene class, however, it effects repression by targeting distinct temporal events and components of transcriptional machinery

2018-02-28 | GSE109131 | GEO

Total RNA Pol2 ChIP-seq in mES cells treated with flavopiridol (Cdk9 inhibitor) after DSIF and NELF knockdown

2011-01-19 | GSE26658 | GEO

Enhancer RNAs stimulate Pol II pause release by harnessing multivalent interactions to NELF

Project description:UV-light-induced protein-RNA cross-linking followed by MS analysis was used to identify RNA-binding regions of enhancer RNAs (eRNAs) to the negative elongation factor (NELF) complex, and NELF as part of the paused elongation complex (PEC) of human RNA polymerase II.

2022-03-08 | PXD030569 | Pride

Total RNA Pol2 ChIP-seq in mES cells treated with flavopiridol (Cdk9 inhibitor) after DSIF and NELF knockdown

Project description:Recent studies have found that promoter-proximal pausing occurs at most Pol2-regulated genes. DSIF and NELF function as negative elongation factors and promote Pol2 pausing. P-TEFb, whose enzymatic activity lies in the kinase Cdk9, positively regulates the transition into productive elongation by phosphorylating subunits in DSIF, NELF and Pol2. To gain insights into the interplay between these factors in regulating transcriptional pause release, we tested if knockdown of either pausing factor could bypass P-TEFb function. We find that P-TEFb function is still required for transcriptional elongation after DSIF or NELF knockdown. mES cells were infected with a shRNA hairpin to knockdown Spt5, Spt4, NelfE or control. The resulting cells were then treated with flavopiridol (1uM for 60 minutes). DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing. A sample of whole cell extract was sequenced and used as the background to determine enrichment. ChIP was performed using an antibody against total RNA Pol2 (Rpb1 N-terminus, Santa Cruz sc-899).

2011-01-19 | E-GEOD-26658 | biostudies-arrayexpress

Promoter-specific changes in initiation, elongation and homeostasis of histone H3 acetylation during CBP/p300 Inhibition [GRO-Seq]

Project description:Regulation of RNA Polymerase II (Pol2) elongation in the promoter proximal region is an important and ubiquitous control point for gene expression in metazoans. We report that transcription of the adenovirus 5 E4 region is regulated during the release of paused Pol2 into productive elongation by recruitment of the super elongation complex (SEC), dependent on promoter H3K18/27 acetylation by CBP/p300. We also establish that this is a general transcriptional regulatory mechanism that applies to ~6% of expressed protein-coding genes in primary human airway epithelial cells. We observed that a homeostatic mechanism maintains promoter, but not enhancer H3K18/27ac in response to extensive inhibition of CBP/p300 acetyl transferase activity by the highly specific small molecule inhibitor A-485. Further, our results suggest a function for BRD4 association at enhancers in regulating paused Pol2 release at nearby promoters. Taken together, our results uncover processes regulating transcriptional elongation by promoter region histone H3 acetylation and homeostatic maintenance of promoter, but not enhancer, H3K18/27ac in response to inhibition of CBP/p300 acetyl transferase activity.

2021-03-01 | GSE167092 | GEO

Promoter-specific changes in initiation, elongation and homeostasis of histone H3 acetylation during CBP/p300 Inhibition [ChIP-Seq]

2021-03-01 | GSE167091 | GEO

SPT6 functions in transcriptional pause-release via PAF1C recruitment [PRO-seq]

Project description:In vitro studies identified various factors including P-TEFb, SEC, SPT6, PAF1, DSIF, and NELF functioning at different stages of transcription elongation driven by RNA polymerase II (RNA Pol II). What remains unclear is how these factors cooperatively regulate pause/release and productive elongation in the context of living cells. Using an acute protein-depletion approach, we report that SPT6 depletion results in release of paused RNA Pol II. Short genes demonstrate a prominent release and a subsequent increase in mature transcripts, whereas long genes fail to yield mature transcripts due to a loss of processivity. Unexpectedly, the recruitment of PAF1 complex (PAF1C) to RNA Pol II fails upon SPT6 depletion, leading to the release of NELF-bound RNA Pol II into the gene bodies. Furthermore, SPT6 depletion impairs heat shock-induced pausing, pointing to a role for SPT6 in regulating RNA Pol II pause-release through PAF1C recruitment and NELF removal during the early elongation.

2022-08-09 | GSE202187 | GEO

SPT6 functions in transcriptional pause-release via PAF1C recruitment [RNA-seq]

2022-08-09 | GSE202189 | GEO

SPT6 functions in transcriptional pause-release via PAF1C recruitment [ChIP-seq]

2022-08-09 | GSE202184 | GEO

NELF regulates a promoter-proximal step distinct from RNA Pol II pause-release

Project description:RNA polymerase II (Pol II) is generally paused at promoter-proximal regions in most metazoans, and based on in vitro studies, this function has been attributed to the negative elongation factor (NELF). Here, we show that upon rapid depletion of NELF, Pol II fails to be released into gene bodies, stopping instead around the +1 nucleosomal dyad-associated region. The transition to the 2nd pause region is independent of positive transcription elongation factor P-TEFb. During the heat shock response, Pol II is rapidly released from pausing at heat shock induced genes, while most genes are paused and transcriptionally downregulated during the heat shock response. We find that both aspects of the heat shock response remain intact upon NELF loss. We find that NELF depletion results in global loss of cap-binding complex from chromatin without global reduction of nascent transcript 5’ cap stability. Thus, our studies implicate NELF functioning in early elongation complexes distinct from Pol II pause-release.

2020-03-09 | GSE144786 | GEO

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