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PTEN modulates gene transcription by redistributing genome-wide RNA polymerase II occupancy [ChIP-seq]

ABSTRACT: Control of gene expression is one of the most complex yet continuous physiological processes impacting cellular homeostasis. RNA polymerase II (Pol II) transcription is tightly regulated at promoter-proximal regions by intricate dynamic processes including Pol II pausing, release into elongation, and premature termination. Here, we identify PTEN interacting with the Pol II transcription machinery and dephosphorylating Pol II C-terminal domain in vitro. PTEN alters the expression of hundreds of genes, and its restoration establishes Pol II promoter-proximal pausing in PTEN null cells. Furthermore, PTEN re-distributes genome-wide Pol II occupancy and possibly impacts Pol II pause duration, release, and elongation rate in order to enable precise gene regulation at genome-wide scale. Our observations demonstrate a direct and imperative role of PTEN in global transcriptional regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124657 | GEO | 2019/06/04

REPOSITORIES: GEO

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PTEN modulates gene transcription by redistributing genome-wide RNA polymerase II occupancy [RNA-seq]

Project description:Control of gene expression is one of the most complex yet continuous physiological processes impacting cellular homeostasis. RNA polymerase II (Pol II) transcription is tightly regulated at promoter-proximal regions by intricate dynamic processes including Pol II pausing, release into elongation, and premature termination. Here, we identify PTEN interacting with the Pol II transcription machinery and dephosphorylating Pol II C-terminal domain in vitro. PTEN alters the expression of hundreds of genes, and its restoration establishes Pol II promoter-proximal pausing in PTEN null cells. Furthermore, PTEN re-distributes genome-wide Pol II occupancy and possibly impacts Pol II pause duration, release, and elongation rate in order to enable precise gene regulation at genome-wide scale. Our observations demonstrate a direct and imperative role of PTEN in global transcriptional regulation.

2019-06-04 | GSE124658 | GEO

PAF1, a molecular regulator of promoter-proximal pausing by RNA Polymerase II

Project description:The control of promoter-proximal pausing and the release of RNA polymerase II (RNA Pol II) is a widely used mechanism for regulating gene expression in metazoans, especially for genes that respond to environmental and developmental cues. Here, we identify Pol II associated Factor 1 (PAF1) as a major regulator of promoter-proximal pausing. Knockdown of PAF1 leads to increased release of paused Pol II into gene bodies at thousands of genes. Genes with the highest levels of paused Pol II exhibit the largest redistribution of Pol II from the promoter-proximal region into the gene body in the absence of PAF1. PAF1 depletion results in increased nascent transcription and increased levels of phosphorylation of Pol II’s c-terminal domain on serine 2 (Ser2P). These changes can be explained by the recruitment of the Ser2P kinase Super Elongation Complex (SEC) effecting increased release of paused Pol II into productive elongation, thus establishing a novel function for PAF1 as a major regulator of pausing in metazoans.

2015-08-13 | GSE70408 | GEO

PAF1, a molecular regulator of promoter-proximal pausing by RNA Polymerase II

2015-08-13 | E-GEOD-70408 | biostudies-arrayexpress

RNA Polymerase II-associated factor 1 regulates the release and phosphorylation of paused RNA Polymerase II

Project description:Release of promoter-proximal paused RNA polymerase II (Pol II) during early elongation is a critical step in transcriptional regulation in metazoan cells. Paused Pol II release is thought to require the kinase activity of cyclin-dependent kinase 9 (CDK9) for the phosphorylation of DRB sensitivity-inducing factor, negative elongation factor, and C-terminal domain (CTD) serine-2 of Pol II. We found that Pol II-associated factor 1 (PAF1) is a critical regulator of paused Pol II release, that positive transcription elongation factor b (P-TEFb) directly regulates the initial recruitment of PAF1 complex (PAF1C) to genes, and that the subsequent recruitment of CDK12 is dependent on PAF1C. These findings reveal cooperativity among P-TEFb, PAF1C, and CDK12 in pausing release and Pol II CTD phosphorylation.

2015-12-11 | GSE62171 | GEO

RNA Polymerase II-associated factor 1 regulates the release and phosphorylation of paused RNA Polymerase II

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PAF1 regulation of promoter-proximal pause release via enhancer activation

Project description:Gene expression in metazoans is regulated by RNA Polymerase II (Pol II) promoter-proximal pausing and its release. Previously, we identified that Pol II-associated factor 1 (PAF1) modulates the release of paused Pol II into productive elongation. Here, we find that PAF1 occupies transcriptional enhancers and restrains hyperactivation of a subset of these enhancers. Enhancer activation as the result of Paf1 loss releases Pol II from paused promoters of nearby PAF1 target genes. Knockout of PAF1-regulated enhancers attenuates the release of paused Pol II on PAF1 target genes without major interference in the establishment of pausing at their cognate promoters. Thus, a subset of enhancers can primarily modulate gene expression by controlling the release of paused Pol II in a PAF1-dependent manner.

2017-09-01 | GSE97527 | GEO

The histone deacetylase SIRT6 controls transcription elongation via promoter-proximal pausing (PRO-Seq)

Project description:Transcriptional regulation in eukaryotes commonly occurs at promoter-proximal regions wherein transcriptionally engaged RNA Polymerase II (Pol II) pauses before proceeding towards productive elongation. The roles of chromatin in this process remains poorly understood. Here, we demonstrate that the histone deacetylase SIRT6 regulates transcription elongation by binding to Pol II and anchoring the Negative ELongation Factor NELF, thereby preventing the release of Pol II towards elongation. Absence of SIRT6, or conditions of glucose deprivation, lead to increased levels of acetylated histone H3 at lysines 9 (H3K9ac) and 56 (H3K56ac), activation of the CDK9 kinase, phosphorylation of NELF and Pol II, and recruitment of the transcription factors MYC and BRD4, the PAF1 Complex, as well as several positive elongation factors, in turn releasing Pol II into productive elongation. Collectively, we identified SIRT6 as the first pausing-dedicated histone deacetylase, regulating intragenic H3K9ac and H3K56ac as critical chromatin modifications modulating transcriptional pausing and elongation.

2019-10-31 | GSE130691 | GEO

The histone deacetylase SIRT6 controls transcription elongation via promoter- proximal pausing (RNA-Seq)

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The histone deacetylase SIRT6 controls transcription elongation via promoter- proximal pausing (ChIP-Seq)

2019-10-31 | GSE130689 | GEO

RNA Polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation [NET-seq]

Project description:The controlled release of promoter-proximal RNA polymerase II (Pol II) pausing into productive elongation is a major step in gene regulation. Yet, functionally analyzing Pol II pausing is difficult because the factors that regulate pause release are generally essential. Here, we identified heterozygous loss-of-function mutations in SUPT5H, encoding SPT5, in individuals with β-thalassemia trait unlinked to the β-globin locus. Recapitulating the pathogenic mutations in human erythroid cells or acute treatment with transcription inhibitors replicates the patient phenotype of altered globin gene expression. Furthermore, in SUPT5H-edited cells, Pol II pause release was globally disrupted. We observed dynamic patterns of pausing at cell cycle and erythroid differentiation genes at the transition from progenitors to precursors during erythropoiesis. At this same transition, in SUPT5H-edited cells, we observed delayed differentiation and altered cell cycle kinetics, as well as a delay in the onset of gene expression programs. Therefore, hindering pause release perturbs cell cycle and delays differentiation at key stages of erythropoiesis, revealing a role for Pol II pausing in the temporal coordination between the cell cycle and differentiation.

2023-07-21 | GSE214557 | GEO

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