BRD4 in physiology and pathology: ‘‘BET’’ on its partners

Liang, Yin; Tian, Jieyi; Wu, Tao

doi:10.1002/bies.202100180

Cited by 34 publications

(31 citation statements)

References 136 publications

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“…As present BET inhibitors, including JQ1, could not effectively distinguish BRD2, BRD3, BRD4, and BRDT [39], we also determined the expression of BRD2, BRD3 and BRD4, and the results showed that both the mRNA and protein levels of BRD2, BRD3 and BRD4 were upregulated by LPS injection, and JQ1 administration reduced the expression of BRD2, BRD3 and BRD4. Since BRDT is speci cally expressed in the testis [40], we did not check its expression.…”

Section: Discussionmentioning

confidence: 99%

JQ1 attenuates neuroinflammation by inhibiting the inflammasome-dependent canonical pyroptosis pathway in SAE

Zhong

Chen

Wang

et al. 2022

Preprint

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Sepsis-associated encephalopathy (SAE) manifests clinically in hyperneuroinflammation. Pyroptosis, which can induce an inflammatory cascade response, has been considered to be a causative factor of SAE. Evidence has shown that the bromo- and extraterminal (BET) proteins (including BRD2, BRD3, BRD4 and BRDT) inhibitor JQ1 can inhibit inflammation and suppress pyroptosis in various diseases. Therefore, we examined the effect of JQ1 on inflammasome-induced pyroptosis in the hippocampus in a mouse model of sepsis induced by lipopolysaccharide (LPS) injection. The results showed that JQ1 treatment alleviated sepsis-related symptoms, protected the blood–brain barrier (BBB), as indicated by upregulated expression of the tight junction proteins occludin and ZO-1, and remarkably rescued neuronal damage in SAE mice. Mechanistically, we demonstrated that JQ1 intervention inhibited the expression of BRD proteins and decreased the expression of inflammasomes by blocking nuclear factor kappa B (NFκB) signalling, attenuating the canonical pyroptosis (mediated by cleaved-Caspase1/11) pathway and the release of proinflammatory factors in the hippocampus of septic mice. Interestingly, we also found that JQ1 selectively suppressed the activation of hippocampal microglia in SAE mice. Thus, JQ1 protected the hippocampal BBB and neuronal damage through the attenuation of neuroinflammation by inhibiting the inflammasome-dependent canonical pyroptosis pathway induced by LPS injection in mice, and JQ1 may be a promising target for the prevention of SAE.

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Section: Discussionmentioning

confidence: 99%

JQ1 attenuates neuroinflammation by inhibiting the inflammasome-dependent canonical pyroptosis pathway in SAE

Zhong

Chen

Wang

et al. 2022

Preprint

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“…Recent data from an animal study have shown that deletion of thioredoxin reductase-1 (Txnrd1), which is critical for the last step of nucleotide biosynthesis, precludes the expansion of DN cells ( 88 ). c-Myc gene expression is also regulated by bromodomain protein 4 (BRD4), which is a transcriptional and epigenetic regulator with functions throughout the cell cycle for proliferative regulation ( 89 – 93 ). It has been shown that BRD4 governs the development and differentiation of ISP thymocytes by modulating metabolic pathways and cell cycle progression ( 94 ).…”

Section: β-Selected Thymocytes Exhibit Robust Cell Proliferation and ...mentioning

confidence: 99%

Metabolic regulation of T cell development

Zhang

Lin²,

Zhang³

et al. 2022

Front. Immunol.

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T cell development in the thymus is tightly controlled by complex regulatory mechanisms at multiple checkpoints. Currently, many studies have focused on the transcriptional and posttranslational control of the intrathymic journey of T-cell precursors. However, over the last few years, compelling evidence has highlighted cell metabolism as a critical regulator in this process. Different thymocyte subsets are directed by distinct metabolic pathways and signaling networks to match the specific functional requirements of the stage. Here, we epitomize these metabolic alterations during the development of a T cell and review several recent works that provide insights into equilibrating metabolic quiescence and activation programs. Ultimately, understanding the interplay between cellular metabolism and T cell developmental programs may offer an opportunity to selectively regulate T cell subset functions and to provide potential novel therapeutic approaches to modulate autoimmunity.

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“…Similarly, IMPDH2 (Inosine-5-monophosphate dehydrogenase 2) showed high expression in lung macrophages and medium expression in respiratory epithelial cells of the nasopharynx and bronchus. BRD4 is a member of the Bromo and Extra Terminal (BET) family of proteins that bind acetylated histones and play roles in regulation of transcription, DNA repair, and replication (29,30). In transcription, BRD4 is involved in activation of multiple genes, including those central to proinflammatory and host immune responses (31)(32)(33).…”

Section: Selection Of a Subset Of Host Targets That Is Most Relevant ...mentioning

confidence: 99%

Discovery of host-directed modulators of virus infection by probing the SARS-CoV-2-host protein-protein interaction network

Ravindran

Wagoner

Athanasiadis

et al. 2022

Preprint

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The ongoing coronavirus disease 2019 (COVID-19) pandemic has highlighted the need to better understand virus-host interactions. We developed a network-based algorithm that expands the SARS-CoV-2-host protein interaction network and identifies host targets that modulate viral infection. To disrupt the SARS-CoV-2 interactome, we systematically probed for potent compounds that selectively target the identified host proteins with high expression in cells relevant to COVID-19. We experimentally tested seven chemical inhibitors of the identified host proteins for modulation of SARS-CoV-2 infection in human cells that express ACE2 and TMPRSS2. Inhibition of the epigenetic regulators bromodomain-containing protein 4 (BRD4) and histone deacetylase 2 (HDAC2), along with ubiquitin specific peptidase (USP10), enhanced SARS-CoV-2 infection. Such proviral effect was observed upon treatment with compounds JQ1, vorinostat, romidepsin, and spautin-1, when measured by cytopathic effect and validated by viral RNA assays, suggesting that HDAC2, BRD4 and USP10 host proteins have antiviral functions. The network-based approach enables systematic identification of host-targets that selectively modulate the SARS-CoV-2 interactome, as well as reveal novel chemical tools to probe virus-host interactions that regulate virus infection.

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BRD4 in physiology and pathology: ‘‘BET’’ on its partners

Cited by 34 publications

References 136 publications

JQ1 attenuates neuroinflammation by inhibiting the inflammasome-dependent canonical pyroptosis pathway in SAE

JQ1 attenuates neuroinflammation by inhibiting the inflammasome-dependent canonical pyroptosis pathway in SAE

Metabolic regulation of T cell development

Discovery of host-directed modulators of virus infection by probing the SARS-CoV-2-host protein-protein interaction network

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