Epigenetic and pharmacological control of pigmentation via Bromodomain Protein 9 (<scp>BRD9</scp>)

Basuroy, Tupa; Dreier, Megan R.; Baum, Caitlin E.; Blomquist, Thomas M.; Trumbly, Robert; Filipp, Fabian V.; Serna, Ivana L. de la

doi:10.1111/pcmr.13068

Cited by 3 publications

(2 citation statements)

References 79 publications

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“…However, the requirement for other mSWI/SNF sub-families was not determined for these processes. ncBAF was reported to regulate pluripotency in mouse ES cells [23], and the Brd9 component of ncBAF was required for pigment specific gene expression during melanocyte differentiation [80], but little else is known outside the context of cancer. At present, general conclusions about the roles of the different sub-families are not possible.…”

Section: Discussionmentioning

confidence: 99%

Differential Contributions of mSWI/SNF Chromatin Remodeler Sub-Families to Myoblast Differentiation

Padilla‐Benavides

Olea-Flores

Sharma

et al. 2023

IJMS

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Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodeling enzymes that are critical for normal cellular functions. mSWI/SNF enzymes are classified into three sub-families based on the presence of specific subunit proteins. The sub-families are Brm- or Brg1-associated factor (BAF), ncBAF (non-canonical BAF), and polybromo-associated BAF (PBAF). The biological roles for the different enzyme sub-families are poorly described. We knocked down the expression of genes encoding unique subunit proteins for each sub-family, Baf250A, Brd9, and Baf180, which mark the BAF, ncBAF, and PBAF sub-families, respectively, and examined the requirement for each in myoblast differentiation. We found that Baf250A and the BAF complex were required to drive lineage-specific gene expression. KD of Brd9 delayed differentiation. However, while the Baf250A-dependent gene expression profile included myogenic genes, the Brd9-dependent gene expression profile did not, suggesting Brd9 and the ncBAF complex indirectly contributed to differentiation. Baf180 was dispensable for myoblast differentiation. The results distinguish between the roles of the mSWI/SNF enzyme sub-families during myoblast differentiation.

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Section: Discussionmentioning

confidence: 99%

Differential Contributions of mSWI/SNF Chromatin Remodeler Sub-Families to Myoblast Differentiation

Padilla‐Benavides

Olea-Flores

Sharma

et al. 2023

IJMS

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“…The first of these drugs to be characterized was PFI-3, which selectively binds to the bromodomains of SMARCA4, SMARCA2, and PBRM1 [151]. PFI-3-compromised embryonic stem cell maintenance and lineage specification, inhibited myogenesis and adipogenesis, and had mild effects on melanogenesis [152][153][154][155]. However, the inhibition with PFI-3 as a single drug had limited effects on breast cancer cell proliferation [156].…”

Section: Targeting Swi/snf Family VIII Bromodomainsmentioning

confidence: 99%

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Dreier,

Walia,

de la Serna

2024

Epigenomes

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SWI/SNF enzymes are heterogeneous multi-subunit complexes that utilize the energy from ATP hydrolysis to remodel chromatin structure, facilitating transcription, DNA replication, and repair. In mammalian cells, distinct sub-complexes, including cBAF, ncBAF, and PBAF exhibit varying subunit compositions and have different genomic functions. Alterations in the SWI/SNF complex and sub-complex functions are a prominent feature in cancer, making them attractive targets for therapeutic intervention. Current strategies in cancer therapeutics involve the use of pharmacological agents designed to bind and disrupt the activity of SWI/SNF complexes or specific sub-complexes. Inhibitors targeting the catalytic subunits, SMARCA4/2, and small molecules binding SWI/SNF bromodomains are the primary approaches for suppressing SWI/SNF function. Proteolysis-targeting chimeras (PROTACs) were generated by the covalent linkage of the bromodomain or ATPase-binding ligand to an E3 ligase-binding moiety. This engineered connection promotes the degradation of specific SWI/SNF subunits, enhancing and extending the impact of this pharmacological intervention in some cases. Extensive preclinical studies have underscored the therapeutic potential of these drugs across diverse cancer types. Encouragingly, some of these agents have progressed from preclinical research to clinical trials, indicating a promising stride toward the development of effective cancer therapeutics targeting SWI/SNF complex and sub-complex functions.

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Epigenetic and pharmacological control of pigmentation via Bromodomain Protein 9 (BRD9)

Basuroy

Dreier

Baum

et al. 2022

Pigment Cell Melanoma Res

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Lineage-specific differentiation programs are activated by epigenetic changes in chromatin structure. Melanin-producing melanocytes maintain a gene expression program ensuring appropriate enzymatic conversion of metabolites into the pigment, melanin, and transfer to surrounding cells. During neuroectodermal development, SMARCA4 (BRG1), the catalytic subunit of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes, is essential for lineage specification. SMARCA4 is also required for development of multipotent neural crest precursors into melanoblasts, which differentiate into pigment-producing melanocytes. In addition to the catalytic domain, SMARCA4 and several SWI/SNF subunits contain bromodomains which are amenable to pharmacological inhibition. We investigated the effects of pharmacological inhibitors of SWI/SNF bromodomains on melanocyte differentiation. Strikingly, treatment of murine melanoblasts and human neonatal epidermal melanocytes with selected bromodomain inhibitors abrogated melanin synthesis and visible pigmentation. Using functional genomics, iBRD9, a small molecule selective for the bromodomain of BRD9 was found to repress pigmentation-specific gene expression. Depletion of BRD9 confirmed a requirement for expression of pigmentation genes in the differentiation program from melanoblasts into pigmented melanocytes and in melanoma cells. Chromatin immunoprecipitation assays showed that iBRD9 disrupts the occupancy of BRD9 and the catalytic subunit SMARCA4 at melanocyte-specific loci.These data indicate that BRD9 promotes melanocyte pigmentation whereas pharmacological inhibition of BRD9 is repressive.

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Epigenetic and pharmacological control of pigmentation via Bromodomain Protein 9 (BRD9)

Cited by 3 publications

References 79 publications

Differential Contributions of mSWI/SNF Chromatin Remodeler Sub-Families to Myoblast Differentiation

Differential Contributions of mSWI/SNF Chromatin Remodeler Sub-Families to Myoblast Differentiation

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Epigenetic and pharmacological control of pigmentation via Bromodomain Protein 9 (BRD9)

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