Bromodomain 4: a cellular Swiss army knife

Devaiah, Ballachanda N.; Gégonne, Anne; Singer, Dinah S.

doi:10.1189/jlb.2ri0616-250r

Cited by 97 publications

(90 citation statements)

References 68 publications

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“…(4,45) Our results, showing that a Brd4 mutation (Met149Thr) is associated with renal calcification in the RCALC1 mice, also reveal a new pathogenic role for the encoded protein, BRD4, which plays a critical role in regulating gene transcription by binding to modified histone tails of chromosomal DNA and recruiting transcriptional activating proteins. (51)(52)(53)(54) Our structural studies demonstrated that mutation of Met149 to Thr149 is likely to affect protein structure (Fig. 2), and previous studies have shown the Met149 residue to be required for histone binding.…”

Section: Journal Of Bone and Mineral Researchsupporting

confidence: 63%

“…2D). (51)(52)(53)(54) The Met149 residue is located in the aC-helix of BRD4 BD1 (Fig. 2E), and previous studies have shown that Met149 is critical for histone binding and that mutation to Ala149 impairs this binding.…”

Section: Characterization Of the Brd4-met149thr Variant On Protein Stmentioning

confidence: 58%

“…The BRD4 protein plays a critical role in transcriptional activation by binding to acetylated histone tails using its tandem bromodomains (BD) BD1 and BD2, and regulates transcription by recruiting proteins involved in nuclear remodeling using its extraterminal (ET) domain and its C‐terminal interaction motif (CTM) (Fig. D ) . The Met149 residue is located in the αC‐helix of BRD4 BD1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis

Gorvin

Loh

Stechman

et al. 2019

Journal of Bone and Mineral Research

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Nephrolithiasis (NL) and nephrocalcinosis (NC), which comprise renal calcification of the collecting system and parenchyma, respectively, have a multifactorial etiology with environmental and genetic determinants and affect ∼10% of adults by age 70 years. Studies of families with hereditary NL and NC have identified >30 causative genes that have increased our understanding of extracellular calcium homeostasis and renal tubular transport of calcium. However, these account for <20% of the likely genes that are involved, and to identify novel genes for renal calcification disorders, we investigated 1745 12‐month‐old progeny from a male mouse that had been treated with the chemical mutagen N‐ethyl‐N‐nitrosourea (ENU) for radiological renal opacities. This identified a male mouse with renal calcification that was inherited as an autosomal dominant trait with >80% penetrance in 152 progeny. The calcification consisted of calcium phosphate deposits in the renal papillae and was associated with the presence of the urinary macromolecules osteopontin and Tamm‐Horsfall protein, which are features found in Randall's plaques of patients with NC. Genome‐wide mapping located the disease locus to a ∼30 Mbp region on chromosome 17A3.3‐B3 and whole‐exome sequence analysis identified a heterozygous mutation, resulting in a missense substitution (Met149Thr, M149T), in the bromodomain‐containing protein 4 (BRD4). The mutant heterozygous (Brd4+/M149T) mice, when compared with wild‐type (Brd4+/+) mice, were normocalcemic and normophosphatemic, with normal urinary excretions of calcium and phosphate, and had normal bone turnover markers. BRD4 plays a critical role in histone modification and gene transcription, and cDNA expression profiling, using kidneys from Brd4+/M149T and Brd4+/+ mice, revealed differential expression of genes involved in vitamin D metabolism, cell differentiation, and apoptosis. Kidneys from Brd4+/M149T mice also had increased apoptosis at sites of calcification within the renal papillae. Thus, our studies have established a mouse model, due to a Brd4 Met149Thr mutation, for inherited NC. © 2019 American Society for Bone and Mineral Research.

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Section: Journal Of Bone and Mineral Researchsupporting

confidence: 63%

Section: Characterization Of the Brd4-met149thr Variant On Protein Stmentioning

confidence: 58%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis

Gorvin

Loh

Stechman

et al. 2019

Journal of Bone and Mineral Research

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“…Brd4 is known to influence transcription by direct and indirect mechanisms leading to the phosphorylation of RNA polymerase II (Pol II) (Devaiah et al, 2016b). For this, it recruits transcription initiation and elongation factors including Mediator and P-TEFb as well as Top I, which in turn stimulates transcription by releasing pausing of Pol II at the promoter-proximal region (McBride and Jang, 2013).…”

Section: Introductionmentioning

confidence: 99%

Involvement of Brd4 in different steps of the papillomavirus life cycle

Iftner¹,

Haedicke‐Jarboui²,

et al. 2017

Virus Research

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Bromodomain-containing protein 4 (Brd4) is a cellular chromatin-binding factor and transcriptional regulator that recruits sequence-specific transcription factors and chromatin modulators to control target gene transcription. Papillomaviruses (PVs) have evolved to hijack Brd4’s activity in order to create a facilitating environment for the viral life cycle. Brd4, in association with the major viral regulatory protein E2, is involved in multiple steps of the PV life cycle including replication initiation, viral gene transcription, and viral genome segregation and maintenance. Phosphorylation of Brd4, regulated by casein kinase II (CK2) and protein phosphatase 2A (PP2A), is critical for viral gene transcription as well as E1- and E2-dependent origin replication. Thus, pharmacological agents regulating Brd4 phosphorylation and inhibitors blocking phospho-Brd4 functions are promising candidates for therapeutic intervention in treating human papillomavirus (HPV) infections as well as associated disease.

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“…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].…”

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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Bromodomain 4: a cellular Swiss army knife

Cited by 97 publications

References 68 publications

Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis

Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis

Involvement of Brd4 in different steps of the papillomavirus life cycle

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

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