Enhancer and super‐enhancer: Positive regulators in gene transcription

Peng, Yanling; Zhang, Yubo

doi:10.1002/ame2.12032

Cited by 57 publications

(45 citation statements)

References 147 publications

(217 reference statements)

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“…SE was primarily isolated via the Rank Ordering of SE (ROSE) algorithm in murine embryonic stem cells (ESCs) in 2013 [3,4]. It is strongly occupied with aberrant high levels of master transcription factors (TFs) (Oct4, Sox2 and Nanog), active histone marks [histone H3 lysine 4 monomethylation (H3K4me1), histone H3 lysine 27 acetylation (H3K27ac)], and transcription regulator factors (cyclin-dependent kinases (CDK)7, Mediator (MED)1, bromodomaincontaining protein 4 (BRD4), polymerase II (Pol II) and p300) [5,6]. Currently, SE identification is mainly dependent on chromatin immunoprecipitation followed by sequence analysis (CHIP-seq) [7,8].…”

Section: Introductionmentioning

confidence: 99%

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

Tan

Tang

2020

Mol Cancer

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seRNA is a noncoding RNA (ncRNA) transcribed from active super-enhancer (SE), through which SE exerts biological functions and participates in various physiological and pathological processes. seRNA recruits cofactor, RNA polymerase II and mediator to constitute and stabilize chromatin loop SE and promoter region, which regulates target genes transcription. In tumorigenesis, DNA insertion, deletion, translocation, focal amplification and carcinogen factor mediate oncogenic SE generation, meanwhile, oncogenic SE transcribes into tumor-related seRNA, termed as oncogenic seRNA. Oncogenic seRNA participates in tumorigenesis through activating various signal-pathways. The recent reports showed that oncogenic seRNA implicates in a widespread range of cytopathological processes in cancer progression including cell proliferation, apoptosis, autophagy, epithelial-mesenchymal transition, extracellular matrix stiffness and angiogenesis. In this article, we comprehensively summarized seRNA's characteristics and functions, and emphatically introduced inducible formation of oncogenic seRNA and its functional mechanisms. Lastly, some research strategies on oncogenic seRNA were introduced, and the perspectives on cancer therapy that targets oncogenic seRNA were also discussed.

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Section: Introductionmentioning

confidence: 99%

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

Tan

Tang

2020

Mol Cancer

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“…Therefore, we speculated that PAF1, as a Pol IIassociated factor, indirectly regulates the transcription of these enhancers by binding to Pol II, thereby inhibiting the synthesis of eRNA and weakening the long-acting trans-promoting effect of eRNA on the target gene promoter. Considering that eRNA has a low abundance value, the value of the trans-promoting effect of eRNA is debated and needs further study [33]. More importantly, the study also found that the relative occupancy level of PAF1 at the enhancer was much higher than that of Pol II, suggesting that the regulation of PAF1-induced enhancer activity is likely mediated by a mechanism that does not involve Pol II.…”

Section: Discussionmentioning

confidence: 85%

“…A recent report showed that the negative transcriptional regulation of the IER5 gene at its promoter region was abolished, which resulted in increased IER5 transcription upon the IR of HepG2 cells [15]. With the development of tumor genomics, an increased number of activated enhancers have been found in many malignant tumors, promoting gene transcription exponentially in a variety of ways [33]. Coincidentally, such activated enhancers have been found near the IER5 gene locus and rapidly promote transcription of the IER5 gene under the induction of external stimuli in several solid tumors, including CC [16].…”

Section: Discussionmentioning

confidence: 99%

Novel role of PAF1 in attenuating radiosensitivity in cervical cancer by inhibiting IER5 transcription

Zheng

Liu

et al. 2020

Radiat Oncol

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Background: Radiosensitivity is limited in cervical cancer (CC) patients due to acquired radiation resistance. In our previous studies, we found that immediate-early response 5 (IER5) is upregulated in CC cells upon radiation exposure and decreases cell survival by promoting apoptosis. The details on the transcriptional regulation of radiation-induced IER5 expression are unknown. Studies in recent years have suggested that Pol II-associated factor 1 (PAF1) is a pivotal transcription factor for certain genes "induced" during tumor progression. In this study, we investigated the role of PAF1 in regulating IER5 expression during CC radiotherapy. Methods: PAF1 expression in CC cells was measured by western blotting, immunohistochemistry, and qRT-PCR, and the localization of PAF1 and IER5 was determined by immunofluorescence. The effect of PAF1 and IER5 knockdown by siRNA in Siha and Hela cells was studied by western blotting, qRT-PCR, CCK-8 assay, and flow cytometry. The physical interaction of PAF1 with the IER5 promoter and enhancers was confirmed using chromatin immunoprecipitation and qPCR with or without enhancers knockout by CRISPR/Cas9. Results: We confirmed that PAF1 was highly expressed in CC cells and that relatively low expression of IER5 was observed in cells with highly expressed PAF1 in the nucleus. PAF1 knockdown in Siha and Hela cells was associated with increased expression of IER5, reduced cell viability and higher apoptosis rate in response to radiation exposure, while simultaneous PAF1 and IER5 knockdown had little effect on the proportion of apoptotic cells. We also found that PAF1 hindered the transcription of IER5 by promoting Pol II pausing at the promoter-proximal region, which was primarily due to the binding of PAF1 at the enhancers. Conclusions: PAF1 reduces CC radiosensitivity by inhibiting IER5 transcription, at least in part by regulating its enhancers. PAF1 might be a potential therapeutic target for overcoming radiation resistance in CC patients.

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“…Among the most prominent of long-range chromatin interactions in ES cells are those of clusters of enhancers that function together, known as super-enhancers (also referred to as stretch enhancers) (Parker et al, 2013;Peng & Zhang, 2018). Super-enhancers are prevalent in ES cells, and are reorganized upon exit from a pluripotent state to facilitate cellular differentiation and specification, as shown through promoter capture experiments (Novo et al, 2018).…”

Section: Long-range Chromatin Interactions Are Critical For Regulatiomentioning

confidence: 99%

Chromatin regulation and dynamics in stem cells

Klein

Hainer

2020

Current Topics in Developmental Biology

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In eukaryotes, DNA is highly compacted within the nucleus into a structure known as chromatin. Modulation of chromatin structure allows for precise regulation of gene expression, and thereby controls cell fate decisions. Specific chromatin organization is established and preserved by numerous factors to generate desired cellular outcomes. In embryonic stem (ES) cells, chromatin is precisely regulated to preserve their two defining characteristics: self-renewal and pluripotent state. This action is accomplished by a litany of nucleosome remodelers, histone variants, epigenetic marks, and other chromatin regulatory factors. These highly dynamic regulatory factors come together to precisely define a chromatin state that is conducive to ES cell maintenance and development, where dysregulation threatens the survival and fitness of the developing organism.

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Enhancer and super‐enhancer: Positive regulators in gene transcription

Cited by 57 publications

References 147 publications

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

Novel role of PAF1 in attenuating radiosensitivity in cervical cancer by inhibiting IER5 transcription

Chromatin regulation and dynamics in stem cells

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