Binding specificity and function of the SWI/SNF subunit SMARCA4 bromodomain interaction with acetylated histone H3K14

Enríquez, Paul; Krajewski, Krzysztof; Strahl, Brian D.; Rothbart, Scott B.; Dowen, Robert H.; Rose, Ray J.

doi:10.1016/j.jbc.2021.101145

Cited by 4 publications

(5 citation statements)

References 77 publications

(146 reference statements)

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“…To validate that our purified BRD Baz2B indeed binds to the acetylated H3 tail peptide, we performed microscale thermophoresis (MST) (Figure 6D ). As expected, BRD Baz2B showed binding to both the acetylated and unmodified H3K14 tail peptides, with binding affinity constants of K D = 16 μM and K D = 288 μM, respectively, consistent with previous ITC and NMR data ( 79 ).…”

Section: Resultssupporting

confidence: 90%

Biochemical and cellular insights into the Baz2B protein, a non-catalytic subunit of the chromatin remodeling complex

Breindl,

Spitzer,

Gerasimaitė

et al. 2023

Nucleic Acids Research

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Baz2B is a regulatory subunit of the ATP-dependent chromatin remodeling complexes BRF1 and BRF5, which control access to DNA during DNA-templated processes. Baz2B has been implicated in several diseases and also in unhealthy ageing, however limited information is available on the domains and cellular roles of Baz2B. To gain more insight into the Baz2B function, we biochemically characterized the TAM (Tip5/ARBP/MBD) domain with the auxiliary AT-hook motifs and the bromodomain (BRD). We observed alterations in histone code recognition in bromodomains carrying cancer-associated point mutations, suggesting their potential involvement in disease. Furthermore, the depletion of Baz2B in the Hap1 cell line resulted in altered cell morphology, reduced colony formation and perturbed transcriptional profiles. Despite that, super-resolution microscopy images revealed no changes in the overall chromatin structure in the absence of Baz2B. These findings provide insights into the biological function of Baz2B.

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Section: Resultssupporting

confidence: 90%

Biochemical and cellular insights into the Baz2B protein, a non-catalytic subunit of the chromatin remodeling complex

Breindl,

Spitzer,

Gerasimaitė

et al. 2023

Nucleic Acids Research

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“…We further delve deeper into the mechanism of MCL in related to BRG1-induced fibrotic responses. As previous studies showed, the binding of BRG1 to acetylated histones H3K14ac is a crucial factor in its gene regulation [ 32 , 33 ]. The role of BRG1-H3K14ac complex in fibrotic responses was explored in vitro.…”

Section: Resultsmentioning

confidence: 99%

“…BRG1 is the central catalytic ATPase of the switch/sucrose nonfermentable chromatin remodeling complex, containing a bromodomain that has been shown to anchor the entire complex to promoter nucleosomes by interacting with histones that are acetylated at specific lysine residues [ 43 , 44 ]. Among that, H3K14ac is a common target for BRG1 recruitment in order to modulate gene regulation [ 32 , 33 ]. In our studies, co-immunoprecipitation analysis reveals that BRG1-H3K14ac complex exists in peritoneal mesothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with our research, Shen et al shows a hydrogen bond between the carbonyl group of N-acetyl in H3K14ac and the side chain amide in N1540 of BRG1 by a molecular dynamics simulation model, revealing the potential interactions BRG1 bromodomain for histone H3K14ac [ 43 ]. In addition, Paul et al reveal that bromodomain of caenorhabditis elegans BRG1 can recognize H3K14ac [ 33 ]. Furthermore, BRG1 can act as a scaffold to recruit various coactivators and corepressors, or histone deacetylase and acetyltransferaseis, to bind and recognize histones acetylation for modulating target genes [ 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

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Brahma-related gene 1 acts as a profibrotic mediator and targeting it by micheliolide ameliorates peritoneal fibrosis

Li,

Luo,

Chen

et al. 2023

J Transl Med

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Background Progressive peritoneal fibrosis is a worldwide public health concern impacting patients undergoing peritoneal dialysis (PD), yet there is no effective treatment. Our previous study revealed that a novel compound, micheliolide (MCL) inhibited peritoneal fibrosis in mice. However, its mechanism remains unclear. Brahma-related gene 1 (BRG1) is a key contributor to organ fibrosis, but its potential function in PD-related peritoneal fibrosis and the relationship between MCL and BRG1 remain unknown. Methods The effects of MCL on BRG1-induced fibrotic responses and TGF-β1-Smads pathway were examined in a mouse PD model and in vitro peritoneal mesothelial cells. To investigate the targeting mechanism of MCL on BRG1, coimmunoprecipitation, MCL-biotin pulldown, molecular docking and cellular thermal shift assay were performed. Results BRG1 was markedly elevated in a mouse PD model and in peritoneal mesothelial cells cultured in TGF-β1 or PD fluid condition. BRG1 overexpression in vitro augmented fibrotic responses and promoted TGF-β1-increased-phosphorylation of Smad2 and Smad3. Meanwhile, knockdown of BRG1 diminished TGF-β1-induced fibrotic responses and blocked TGF-β1-Smad2/3 pathway. MCL ameliorated BRG1 overexpression-induced peritoneal fibrosis and impeded TGF-β1-Smad2/3 signaling pathway both in a mouse PD model and in vitro. Mechanically, MCL impeded BRG1 from recognizing and attaching to histone H3 lysine 14 acetylation by binding to the asparagine (N1540) of BRG1, in thus restraining fibrotic responses and TGF-β1-Smad2/3 signaling pathway. After the mutation of N1540 to alanine (N1540A), MCL was unable to bind to BRG1 and thus, unsuccessful in suppressing BRG1-induced fibrotic responses and TGF-β1-Smad2/3 signaling pathway. Conclusion Our research indicates that BRG1 may be a crucial mediator in peritoneal fibrosis and MCL targeting N1540 residue of BRG1 may be a novel therapeutic strategy to combat PD-related peritoneal fibrosis.

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“…The hydrogen-bonding and hydrophobic interactions are very well conserved in C. elegans SMARCA4 bromodomain and H3 7–20 K14Ac-modified peptide complex. In this case also, the K(Ac)ΦΦR motif is involved in the extensive electrostatic, hydrophobic, and hydrogen-bonding interactions that ensure specific and robust binding between SMARCA4 and H3K14Ac-containing peptides ( Enríquez et al, 2021 ).…”

Section: Acetylationmentioning

confidence: 99%

Catching Nucleosome by Its Decorated Tails Determines Its Functional States

2022

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The fundamental packaging unit of chromatin, i.e., nucleosome, consists of ∼147 bp of DNA wrapped around a histone octamer composed of the core histones, H2A, H2B, H3, and H4, in two copies each. DNA packaged in nucleosomes must be accessible to various machineries, including replication, transcription, and DNA damage repair, implicating the dynamic nature of chromatin even in its compact state. As the tails protrude out of the nucleosome, they are easily accessible to various chromatin-modifying machineries and undergo post-translational modifications (PTMs), thus playing a critical role in epigenetic regulation. PTMs can regulate chromatin states via charge modulation on histones, affecting interaction with various chromatin-associated proteins (CAPs) and DNA. With technological advancement, the list of PTMs is ever-growing along with their writers, readers, and erasers, expanding the complexity of an already intricate epigenetic field. In this review, we discuss how some of the specific PTMs on flexible histone tails affect the nucleosomal structure and regulate the accessibility of chromatin from a mechanistic standpoint and provide structural insights into some newly identified PTM–reader interaction.

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Binding specificity and function of the SWI/SNF subunit SMARCA4 bromodomain interaction with acetylated histone H3K14

Cited by 4 publications

References 77 publications

Biochemical and cellular insights into the Baz2B protein, a non-catalytic subunit of the chromatin remodeling complex

Biochemical and cellular insights into the Baz2B protein, a non-catalytic subunit of the chromatin remodeling complex

Brahma-related gene 1 acts as a profibrotic mediator and targeting it by micheliolide ameliorates peritoneal fibrosis

Catching Nucleosome by Its Decorated Tails Determines Its Functional States

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