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Control of RNA polymerase II promoter-proximal pausing by DNA supercoiling [RNA-seq]

ABSTRACT: During transcription, DNA supercoiling generated by the advance of RNA polymerase II (Pol II) is resolved by DNA topoisomerases, enzymes that bind chromatin and produce transient breaks to relax DNA. Recently, this idea of mere facilitators of transcription progression is changing, as topoisomerases are being assigned new functions in regulating the expression of specific genes. In fact, mammalian type II topoisomerases, both the [Symbol] (TOP2A) and [Symbol] (TOP2B) paralogs, are enriched at promoter regions, where they have been proposed to trigger transcription through the generation of DNA double-strand breaks (DSBs). However, this is difficult to reconcile with the intrinsic catalytic properties of TOP2 and the high risk of genome instability that continuous production and repair of DSBs implies. Here, we show that TOP2A enforces promoter-proximal pausing of Pol II by removing transcription-associated negative DNA supercoiling. Interestingly, this topological balance and its disruption is essential for the transcriptional control of Immediate Early Genes (IEGs) and their typical bursting behaviour in response to stimulus. We therefore uncover a novel layer of transcriptional regulation that relies on canonical functions of TOP2A that are independent of aberrant DSB formation, providing a topological framework for the control of promoter-proximal pausing and the tight regulation of IEGs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141799 | GEO | 2021/04/14

REPOSITORIES: GEO

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Control of RNA polymerase II promoter-proximal pausing by DNA supercoiling [ChIP-seq]

Project description:During transcription, DNA supercoiling generated by the advance of RNA polymerase II (Pol II) is resolved by DNA topoisomerases, enzymes that bind chromatin and produce transient breaks to relax DNA. Recently, this idea of mere facilitators of transcription progression is changing, as topoisomerases are being assigned new functions in regulating the expression of specific genes. In fact, mammalian type II topoisomerases, both the [Symbol] (TOP2A) and [Symbol] (TOP2B) paralogs, are enriched at promoter regions, where they have been proposed to trigger transcription through the generation of DNA double-strand breaks (DSBs). However, this is difficult to reconcile with the intrinsic catalytic properties of TOP2 and the high risk of genome instability that continuous production and repair of DSBs implies. Here, we show that TOP2A enforces promoter-proximal pausing of Pol II by removing transcription-associated negative DNA supercoiling. Interestingly, this topological balance and its disruption is essential for the transcriptional control of Immediate Early Genes (IEGs) and their typical bursting behaviour in response to stimulus. We therefore uncover a novel layer of transcriptional regulation that relies on canonical functions of TOP2A that are independent of aberrant DSB formation, providing a topological framework for the control of promoter-proximal pausing and the tight regulation of IEGs.

2021-04-14 | GSE141798 | GEO

Gene regulation and priming by Topoisomerase IIα in embryonic stem cells [RNA-Seq]

Project description:Topoisomerases are essential for resolving topological problems in the genome, while their function in gene regulation, especially during cellular differentiation, remains unknown. We reveal that the expression of two Topo II isoforms, Top2a and Top2ß, is characteristic of dividing and postmitotic tissues, respectively. In embryonic stem cells, Top2a preferentially binds to promoters embedded in an active chromatin environment. Inhibition of Top2a activity results in misregulation of target gene expression that accompanies accumulation of double-strand breaks. Common targets of Top2a and Top2ß are housekeeping genes while their unique targets are involved in proliferation/pluripotency and neurogenesis, respectively. Moreover, a subset of Top2a targets exhibit bivalent chromatin state that is resolved upon differentiation concomitant with their activation and occupancy by Top2ß, a feature further observed for long genes. These findings suggest that Top2a not only contributes to stem cell transcriptome regulation but may also prime developmental genes for subsequent activation upon differentiation. mRNA profiles of DMSO and ICRF-193 treated mESCs were generated by deep sequencing in triplicates. ICRF-193 is a well established catalytic inhibitor of Topoisomerase II, hence, we used ICRF-193 to the elucidate role of Top2a catalytic activity on transcription by genome wide transcription profiling.

2013-10-10 | E-GEOD-46066 | biostudies-arrayexpress

Gene regulation and priming by Topoisomerase II? in embryonic stem cells [FAIRE-Seq]

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Gene regulation and priming by Topoisomerase IIα in embryonic stem cells [FAIRE-Seq]

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Gene regulation and priming by Topoisomerase IIα in embryonic stem cells [RNA-Seq]

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Transcription dependent dynamic supercoiling in Raji human B cells in vivo

Project description:Transcription has the capacity to modify mechanically DNA topology, DNA structure, and nucleosome arrangement. Resulting from ongoing transcription, these modifications in turn, may provide instant feedback to the transcription machinery. To substantiate the connection between transcription and DNA dynamics, we charted an ENCODE map of transcription-dependent dynamic supercoiling in human Burkitt lymphoma cells using psoralen photobinding to probe DNA topology in vivo. Dynamic supercoils spread ~1.5 kb upstream of the start sites of active genes. Low and high output promoters handle this torsional stress differently as shown using inhibitors of transcription and topoisomerases, and by chromatin immunoprecipation of RNA polymerase and topoisomerases I and II. Whereas lower outputs are managed adequately by topoisomerase I, high output promoters additionally require topoisomerase II. The genome-wide coupling between transcription and DNA topology emphasizes the importance of dynamic supercoiling for gene regulation.

2013-02-16 | GSE43751 | GEO

Transcription dependent dynamic supercoiling in Raji human B cells in vivo

2013-02-16 | E-GEOD-43751 | biostudies-arrayexpress

Transcription forms and remodels supercoiling domains unfolding large scale chromatin structures [NimbleGen ChIP-chip]

Project description:This study was designed to investigate DNA supercoiling across the human genome and to understand how supercoiling domains impact on higher levels of genome organisation. DNA supercoiling is an inherent consequence of twisting DNA and is critical for regulating gene expression and DNA replication. However, DNA supercoiling at a genomic scale in human cells is uncharacterized. To map supercoiling we used biotinylated-trimethylpsoralen as a DNA structure probe to show the genome is organized into supercoiling domains. Domains are formed and remodeled by RNA polymerase and topoisomerase activities and are flanked by GC-AT boundaries and CTCF binding sites. Under-wound domains are transcriptionally active, enriched in topoisomerase I, M-bM-^@M-^\openM-bM-^@M-^] chromatin fibers and DNaseI sites, but are depleted of topoisomerase II. Furthermore DNA supercoiling impacts on additional levels of chromatin compaction as under-wound domains are cytologically decondensed, topologically constrained, and decompacted by transcription of short RNAs. We suggest that supercoiling domains create a topological environment that facilitates gene activation providing an evolutionary purpose for clustering genes along chromosomes. The binding of bTMP, as a reporter for DNA supercoiling, was investigated in RPE1 cells. Experiments were biological replicates

2013-02-17 | E-GEOD-43448 | biostudies-arrayexpress

Transcription forms and remodels supercoiling domains unfolding large scale chromatin structures [Agilent ChIP-chip]

2013-02-17 | E-GEOD-43450 | biostudies-arrayexpress

Transcription forms and remodels supercoiling domains unfolding large scale chromatin structures [Illumina transcription]

Project description:This study was designed to investigate DNA supercoiling across the human genome and to understand how supercoiling domains impact on higher levels of genome organisation. DNA supercoiling is an inherent consequence of twisting DNA and is critical for regulating gene expression and DNA replication. However, DNA supercoiling at a genomic scale in human cells is uncharacterized. To map supercoiling we used biotinylated-trimethylpsoralen as a DNA structure probe to show the genome is organized into supercoiling domains. Domains are formed and remodeled by RNA polymerase and topoisomerase activities and are flanked by GC-AT boundaries and CTCF binding sites. Under-wound domains are transcriptionally active, enriched in topoisomerase I, M-bM-^@M-^\openM-bM-^@M-^] chromatin fibers and DNaseI sites, but are depleted of topoisomerase II. Furthermore DNA supercoiling impacts on additional levels of chromatin compaction as under-wound domains are cytologically decondensed, topologically constrained, and decompacted by transcription of short RNAs. We suggest that supercoiling domains create a topological environment that facilitates gene activation providing an evolutionary purpose for clustering genes along chromosomes. The gene transcription of 3 independent biological replicates were investigated

2013-02-17 | E-GEOD-43449 | biostudies-arrayexpress

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