The Role of Bromodomain and Extraterminal Motif (BET) Proteins in Chromatin Structure

Hsu, Sarah; Blobel, Gerd A.

doi:10.1101/sqb.2017.82.033829

Cited by 39 publications

(37 citation statements)

References 67 publications

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“…Since ZNF281 is involved in inducing epithelial–mesenchymal transition (EMT) and promotes metastatis [52], anti-oncogenic effects of JQ1 on H23 cells may partly be due to downregulation of ZNF281, presumably through dissociation of BRD2, which may lead to disrupted EMT in lung cancer. Interestingly, a recent study showed that BRD2 activates expression of genes involved in EMT induction, whereas BRD3 and BRD4 exert opposite functions [53], supporting distinct roles of BRD2 among the somatic BET proteins [34,35,54,55]. Other TFs identified by MARA but not discussed here may be involved in the BRD2-associated transcriptional regulation.…”

Section: Discussionmentioning

confidence: 53%

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Handoko¹,

Kaczkowski²,

Hon³

et al. 2018

Epigenetics

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The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found that a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and -independent manner.

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Section: Discussionmentioning

confidence: 53%

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Handoko¹,

Kaczkowski²,

Hon³

et al. 2018

Epigenetics

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“…BRD4 is involved in maintaining chromatin structure [12], we investigated whether BRD4 inhibition might induce the DDR to activate innate immunity. Because BRD4 is a histone acetyltransferase [16], we assessed whether BRD4 inhibition might induce changes in genome structure.…”

Section: Brd4 Inhibition Leads To Ddrmentioning

confidence: 99%

“…Bromodomain protein 4 (BRD4) is a reader and writer of histone acetylation that plays important roles in replication, transcription and DNA repair [10,11]. The post-translational modification of histone acetylation is a key mechanism that regulates chromatin organization, and several studies have focused on the important function of BRD4 in regulating chromatin structure [12][13][14][15]. The histone acetyltransferase activity of BRD4 is responsible for maintaining normal chromatin structure [16].…”

mentioning

confidence: 99%

BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses

Wang

Ming

et al. 2020

PLoS Pathog

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Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases. Author summaryBRD4 has been well investigated in tumorigenesis for its contribution to chromatin remodeling and gene transcription. BRD4 inhibitors are used as promising chemotherapeutic drugs for cancer therapy. Here, we show a unique mechanism through which BRD4 inhibition broadly inhibits attachment of DNA and RNA viruses through DNA damage-dependent antiviral innate immune activation via the cGAS-STING pathway, in both cell culture and an animal model. STING-associated innate immune signaling has been considered to be a new possibility for cancer therapy, and STING agonists have been tested in early clinical trials. Our data identify BRD4 inhibitors as a potent therapy not only for viral infection but also for cancer immunotherapy. PLOS PATHOGENSPLOS Pathogens | https://doi.

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“…This implies that enhancer and promoter factors differentially recruit Nipped-B, SA and cohesin. The Mediator complex that regulates transcription (Allen and Taatjes 2015) and the BRD4 BET domain protein that binds acetylated histones (Hsu and Blobel 2017) are candidates for such factors. Mammalian Mediator interacts with NIPBL (Nipped-B) (Kagey et al 2010) and an affinity chromatography-mass spectrometry screen revealed that the Drosophila MED30 Mediator subunit interacts with Nipped-B (Guruharsha et al 2012).…”

Section: The Med30 Mediator Subunit and The Fs(1)h Bet Domain Proteinmentioning

confidence: 99%

Cohesin occupancy and composition at enhancers and promoters are linked to DNA replication origin proximity inDrosophila

Pherson

Misulovin

Gause

et al. 2019

Preprint

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Cohesin consists of the Smc1-Smc3-Rad21 tripartite ring and the SA protein that interacts with Rad21. The Nipped-B protein loads cohesin topologically around chromosomes to mediate sister chromatid cohesion and facilitate long-range control of gene transcription. It is largely unknown how Nipped-B and cohesin associate specifically with gene promoters and transcriptional enhancers, or how sister chromatid cohesion is established. Here we use genome-wide chromatin immunoprecipitation in Drosophila cells to show that SA and the Fs(1)h (BRD4) BET domain protein help recruit Nipped-B and cohesin to enhancers and DNA replication origins, while the MED30 subunit of the Mediator complex directs Nipped-B and Rad21 to promoters. All enhancers and their neighboring promoters are close to DNA replication origins and bind SA with proportional levels of cohesin subunits. Most promoters are far from origins and lack SA, but bind Nipped-B and Rad21 with sub-proportional amounts of Smc1, indicating that they bind SA-deficient cohesin part of the time. Genetic data confirm that Nipped-B and Rad21 function together with Fs(1)h in vivo to facilitate Drosophila development. These findings demonstrate that Nipped-B and cohesin are differentially targeted to enhancers and promoters and suggest models for how SA and DNA replication help establish sister chromatid cohesion and facilitate enhancer-promoter communication. They indicate that SA is not an obligatory cohesin subunit but a factor that controls cohesin location on chromosomes.

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The Role of Bromodomain and Extraterminal Motif (BET) Proteins in Chromatin Structure

Cited by 39 publications

References 67 publications

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses

Cohesin occupancy and composition at enhancers and promoters are linked to DNA replication origin proximity inDrosophila

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