Paused RNA polymerase II inhibits new transcriptional initiation

Shao, Wanqing; Zeitlinger, Julia

doi:10.1038/ng.3867

Cited by 228 publications

(316 citation statements)

References 61 publications

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“…The mechanism of RNAPII pausing has emerged, over the last decade, as a fundamental regulatory step of transcription in higher eukaryotes (Adelman and Lis, 2012). It must be noted that pausing of RNAPII is not simply a brake for transcription, as paused RNAPII in ES cells is required to maintain cell homeostasis and properly respond to environmental stimuli and cues (Henriques et al, 2013; Shao and Zeitlinger, 2017; Williams et al, 2015). In the absence of properly functioning pausing machinery, such as upon depletion of NELF, thousands of genes were shown to respond with transcriptional attenuation (Williams et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

et al. 2018

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Summary AT-rich interactive domain-containing protein 1A and 1B (ARID1A, ARID1B) are mutually exclusive subunits of the chromatin remodeler SWI/SNF. ARID1A is the most frequently mutated chromatin regulator across all cancers, and ovarian clear cell carcinoma (OCCC) carries the highest prevalence of ARID1A mutations (~57%). Despite evidence implicating ARID1A in tumorigenesis, the mechanism remains elusive. Here, we demonstrate that in OCCC ARID1A binds active regulatory elements. Depletion of ARID1A represses RNA Polymerase II (RNAPII) transcription, but results in modest changes to accessibility. Specifically, pausing of RNAPII is severely impaired after loss of ARID1A. Compromised pausing results in transcriptional dysregulation of active genes, which is compensated by upregulation of ARID1B. However, a subset of ARID1A-dependent genes is not rescued by ARID1B, including many p53 and estrogen receptor (ESR1) targets. Our results provide new insight on ARID1A-mediated tumorigenesis and unveil new functions of SWI/SNF in modulating RNAPII dynamics.

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Section: Discussionmentioning

confidence: 99%

The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

et al. 2018

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“…Since P-TEFb-mediated phosphorylation of NELF and the C-terminal domain (CTD) of Pol II are essential for gene expression in mammals (reviewed in 76 ), it is tempting to speculate that increased P-TEFb concentration at the heat-induced genes could overcome the global transcriptional repression. The entry of new Pol II molecules to the TSS is limited by the rate of release of Pol II into productive elongation 77 , as might be expected from the position of the pause site and the size of the Pol II complex, which causes steric hindrance for new initiation 78 . Coupling P-TEFb-mediated pause-release to the entry of new Pol II 78 molecules might be an important mechanism that drives high transcriptional activity, such as that triggered by heat shock.…”

Section: Reprogramming Of Gene Expressionmentioning

confidence: 99%

Molecular mechanisms driving transcriptional stress responses

Vihervaara¹,

Duarte²,

Lis³

2018

Nat Rev Genet

212

224

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Proteotoxic stress, that is, stress caused by protein misfolding and aggregation, triggers the rapid and global reprogramming of transcription at genes and enhancers. Genome-wide assays that track transcriptionally-engaged RNA polymerase II (Pol II) at nucleotide resolution have provided key insights into the underlying molecular mechanisms that regulate transcriptional responses to stress. In addition, recent kinetic analyses on transcriptional control under heat stress have shown how cells ‘prewire’ and rapidly execute genome-wide changes in transcription while concurrently becoming poised for recovery. The regulation of Pol II at genes and enhancers in response to heat stress is coupled to chromatin modification and compartmentalization, as well as to co-transcriptional RNA processing. These mechanistic features seem to apply broadly to other coordinated genome-regulatory responses.

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“…6D). Although it is possible that ZFX regulates release of a paused RNAPII, factors implicated in this process are usually bound at +30 to +40 bp relative to the TSS (Krumm et al 1995;Shao and Zeitlinger 2017). It is unlikely that ZFX is involved in splicing, since the binding site can be in the first exon or at various places within the first intron, depending on the size of the first exon.…”

Section: How Does Zfx Regulate Transcription Of Cpg Island Promoters mentioning

confidence: 99%

ZFX acts as a transcriptional activator in multiple types of human tumors by binding downstream from transcription start sites at the majority of CpG island promoters

et al. 2018

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High expression of the transcription factor ZFX is correlated with proliferation, tumorigenesis, and patient survival in multiple types of human cancers. However, the mechanism by which ZFX influences transcriptional regulation has not been determined. We performed ChIP-seq in four cancer cell lines (representing kidney, colon, prostate, and breast cancers) to identify ZFX binding sites throughout the human genome. We identified roughly 9000 ZFX binding sites and found that most of the sites are in CpG island promoters. Moreover, genes with promoters bound by ZFX are expressed at higher levels than genes with promoters not bound by ZFX. To determine if ZFX contributes to regulation of the promoters to which it is bound, we performed RNA-seq analysis after knockdown of ZFX by siRNA in prostate and breast cancer cells. Many genes with promoters bound by ZFX were down-regulated upon ZFX knockdown, supporting the hypothesis that ZFX acts as a transcriptional activator. Surprisingly, ZFX binds at +240 bp downstream from the TSS of the responsive promoters. Using Nucleosome Occupancy and Methylome Sequencing (NOMe-seq), we show that ZFX binds between the open chromatin region at the TSS and the first downstream nucleosome, suggesting that ZFX may play a critical role in promoter architecture. We have also shown that a closely related zinc finger protein ZNF711 has a similar binding pattern at CpG island promoters, but ZNF711 may play a subordinate role to ZFX. This functional characterization of ZFX provides important new insights into transcription, chromatin structure, and the regulation of the cancer transcriptome.

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Paused RNA polymerase II inhibits new transcriptional initiation

Cited by 228 publications

References 61 publications

The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

Molecular mechanisms driving transcriptional stress responses

ZFX acts as a transcriptional activator in multiple types of human tumors by binding downstream from transcription start sites at the majority of CpG island promoters

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