The molecular basis of selective DNA binding by the BRG1 AT-hook and bromodomain

Sanchez, Julio C.; Zhang, Jintao; Evoli, Stefania; Schnicker, Nicholas; Nunez-Hernandez, Maria; Yu, Liping; Wereszczynski, Jeff; Pufall, Miles A.; Musselman, Catherine A.

doi:10.1016/j.bbagrm.2020.194566

Cited by 16 publications

(19 citation statements)

References 68 publications

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“…Work to date on mSWI/SNF bromodomains has consisted of structural analyses ( 101–105 ), in vitro studies of bromodomain binding to histones, DNA and nucleosomes ( 102 , 105–109 ) and a limited number of functional analyses in higher eukaryotes ( 110 , 111 ). Of particular note, BRG1/BRM bromodomains have specific DNA binding properties that drive association of the proteins with nucleosomes ( 106 , 107 ).…”

Section: Discussionmentioning

confidence: 99%

The Bromodomains of the mammalian SWI/SNF (mSWI/SNF) ATPases Brahma (BRM) and Brahma Related Gene 1 (BRG1) promote chromatin interaction and are critical for skeletal muscle differentiation

Sharma

Robinson

Witwicka

et al. 2021

Nucleic Acids Research

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Skeletal muscle regeneration is mediated by myoblasts that undergo epigenomic changes to establish the gene expression program of differentiated myofibers. mSWI/SNF chromatin remodeling enzymes coordinate with lineage-determining transcription factors to establish the epigenome of differentiated myofibers. Bromodomains bind to acetylated lysines on histone N-terminal tails and other proteins. The mutually exclusive ATPases of mSWI/SNF complexes, BRG1 and BRM, contain bromodomains with undefined functional importance in skeletal muscle differentiation. Pharmacological inhibition of mSWI/SNF bromodomain function using the small molecule PFI-3 reduced differentiation in cell culture and in vivo through decreased myogenic gene expression, while increasing cell cycle-related gene expression and the number of cells remaining in the cell cycle. Comparative gene expression analysis with data from myoblasts depleted of BRG1 or BRM showed that bromodomain function was required for a subset of BRG1- and BRM-dependent gene expression. Reduced binding of BRG1 and BRM after PFI-3 treatment showed that the bromodomain is required for stable chromatin binding at target gene promoters to alter gene expression. Our findings demonstrate that mSWI/SNF ATPase bromodomains permit stable binding of the mSWI/SNF ATPases to promoters required for cell cycle exit and establishment of muscle-specific gene expression.

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Section: Discussionmentioning

confidence: 99%

The Bromodomains of the mammalian SWI/SNF (mSWI/SNF) ATPases Brahma (BRM) and Brahma Related Gene 1 (BRG1) promote chromatin interaction and are critical for skeletal muscle differentiation

Sharma

Robinson

Witwicka

et al. 2021

Nucleic Acids Research

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“…BRD8 (Bromodomain-containing protein 8) is a transcriptional coactivator recruited by hormone nuclear receptors, in which isoforms of BRD8 were reported as the subunit of hNuA4 histone acetyltransferase complex for transcriptional activation (2,48). In addition, BRG1 contains a highly conserved bromodomain at the C-terminus, which might confer a missing ATPase function to the EP400NL complex (49). Given the similarity of the complex composition, it seems feasible in the cells that EP400 and EP400NL may be interchangeable in some specific circumstances of the chromatin remodelling process.…”

Section: Discussionmentioning

confidence: 99%

EP400NL is required for cMyc-mediated PD-L1 gene activation by forming a transcriptional coactivator complex

et al. 2021

Preprint

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EP400 is an ATP-dependent chromatin remodeling enzyme that has been implicated in DNA double-strand break repair and transcription regulation including Myc-dependent gene expression. We previously showed that the N-terminal domain of EP400 increases the efficacy of chemotherapeutic drugs against cancer cells. As the EP400 N-terminal-Like (EP400NL) gene resides next to the EP400 gene locus prompted us to investigate whether EP400NL also plays a similar role in epigenetic transcriptional regulation to the full-length EP400 protein. We found that EP400NL forms a human NuA4-like chromatin remodelling complex that lacks both the TIP60 histone acetyltransferase and EP400 ATPase. However, this EP400NL complex displays H2A.Z deposition activity on a chromatin template comparable to the human NuA4 complex, suggesting another associated ATPase such as BRG1 or RuvBL1/RuvBL2 catalyses the reaction. We also demonstrated that the transcriptional coactivator function of EP400NL is required for cMyc and IFNγ-mediated PD-L1 gene activation. Collectively, our studies show that EP400NL plays a role as a transcription coactivator for cMyc-mediated gene expression and provides a potential target to modulate PD-L1 expression in cancer immunotherapy.

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“…Mutations and deletions of Rb are found in many cancers [121][122][123][124]. Interestingly, SMARCA4 acts primarily as a tumor suppressor, as its loss leads to inactivation of the Rb pathway in ovarian and non-small-cell lung cancers, but is also considered an oncogene in other contexts [125][126][127][128]. Overexpression of SMARCA4 in breast and late-stage pancreatic drives tumor cell proliferation and is associated with progressive disease and poor prognosis [129][130][131].…”

Section: I-motifs In Tumor Suppressor Genesmentioning

confidence: 99%

The i-Motif as a Molecular Target: More Than a Complementary DNA Secondary Structure

Brown

Kendrick

2021

Pharmaceuticals

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Stretches of cytosine-rich DNA are capable of adopting a dynamic secondary structure, the i-motif. When within promoter regions, the i-motif has the potential to act as a molecular switch for controlling gene expression. However, i-motif structures in genomic areas of repetitive nucleotide sequences may play a role in facilitating or hindering expansion of these DNA elements. Despite research on the i-motif trailing behind the complementary G-quadruplex structure, recent discoveries including the identification of a specific i-motif antibody are pushing this field forward. This perspective reviews initial and current work characterizing the i-motif and providing insight into the biological function of this DNA structure, with a focus on how the i-motif can serve as a molecular target for developing new therapeutic approaches to modulate gene expression and extension of repetitive DNA.

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The molecular basis of selective DNA binding by the BRG1 AT-hook and bromodomain

Cited by 16 publications

References 68 publications

The Bromodomains of the mammalian SWI/SNF (mSWI/SNF) ATPases Brahma (BRM) and Brahma Related Gene 1 (BRG1) promote chromatin interaction and are critical for skeletal muscle differentiation

The Bromodomains of the mammalian SWI/SNF (mSWI/SNF) ATPases Brahma (BRM) and Brahma Related Gene 1 (BRG1) promote chromatin interaction and are critical for skeletal muscle differentiation

EP400NL is required for cMyc-mediated PD-L1 gene activation by forming a transcriptional coactivator complex

The i-Motif as a Molecular Target: More Than a Complementary DNA Secondary Structure

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