Altered BAF occupancy and transcription factor dynamics in PBAF-deficient melanoma

Carcamo, Saul; Nguyen, Christie B; Grossi, E; Filipescu, Dan; Alpsoy, Aktan; Dhiman, Alisha; Sun, Dan; Narang, Sonali; Imig, Jochen; Martin, Tiphaine; Parsons, Ramon; Aifantis, Iannis; Tsirigos, Aristotelis; Aguirre‐Ghiso, Julio A.; Dykhuizen, Emily C.; Hasson, Dan; Bernstein, Emily

doi:10.1016/j.celrep.2022.110637

Cited by 24 publications

(28 citation statements)

References 95 publications

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“…Genome-wide data show that BAF occupies enhancer regions, while PBAF is found on both enhancers and promoters (Nakayama et al, 2017;Carcamo et al, 2022). We also found that PBAP occupies both Dad enhancer and promoter (Shidlovskii et al, 2021).…”

Section: Activation Of Rnapii Promoter By Rsc/ Pbap/pbaf Complex Depe...supporting

confidence: 60%

Application of the 3C Method to Study the Developmental Genes in Drosophila Larvae

Bylino

Ibragimov

Digilio³

et al. 2022

Front. Genet.

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A transition from one developmental stage to another is accompanied by activation of developmental programs and corresponding gene ensembles. Changes in the spatial conformation of the corresponding loci are associated with this activation and can be investigated with the help of the Chromosome Conformation Capture (3C) methodology. Application of 3C to specific developmental stages is a sophisticated task. Here, we describe the use of the 3C method to study the spatial organization of developmental loci in Drosophila larvae. We critically analyzed the existing protocols and offered our own solutions and the optimized protocol to overcome limitations. To demonstrate the efficiency of our procedure, we studied the spatial organization of the developmental locus Dad in 3rd instar Drosophila larvae. Differences in locus conformation were found between embryonic cells and living wild-type larvae. We also observed the establishment of novel regulatory interactions in the presence of an adjacent transgene upon activation of its expression in larvae. Our work fills the gap in the application of the 3C method to Drosophila larvae and provides a useful guide for establishing 3C on an animal model.

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Section: Activation Of Rnapii Promoter By Rsc/ Pbap/pbaf Complex Depe...supporting

confidence: 60%

Application of the 3C Method to Study the Developmental Genes in Drosophila Larvae

Bylino

Ibragimov

Digilio³

et al. 2022

Front. Genet.

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“…We also interrogated a recently published dataset of 501MEL cells which had been depleted of the PBAF subunit, ARID2 (Carcamo et al, 2022 ). Of the 94 eGenes that were significantly down‐regulated by iBRD9 in Melb‐a cells, 16 were down‐regulated and 15 were up‐regulated by ARID2 depletion in 501MEL.…”

Section: Resultsmentioning

confidence: 99%

“…It is also not known if BRD9 has an extensive role in regulating melanoma differentiation. On a genomic scale, it was shown that the chromatin alterations which occur upon PBAF loss in melanoma cells are contingent upon the levels of MITF and the identity of the dominant transcription factors (Carcamo et al, 2022 ). Therefore, the suppressive effects of iBRD9 on melanoma differentiation status may not completely parallel those that occur during melanoblast differentiation.…”

Section: Discussionmentioning

confidence: 99%

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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“…Within each SWI/SNF subfamily, the subunits can be arranged in different combinations. The resulting assemblies are key to determine not only the genomic sites of action of the different SWI/SNF complexes, but also their interaction with other transcription factors [ 42 – 45 ], DNA repair proteins [ 31 , 46 ], and DNA replication proteins [ 47 , 48 ], among many others. Increasing evidence has demonstrated that these changes in the SWI/SNF interactome are crucial for the maintenance of hematological gene expression patterns.…”

Section: Swi/snf Complexes and Their Role In Hematopoiesismentioning

confidence: 99%

SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities

et al. 2023

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Hematological malignancies are a highly heterogeneous group of diseases with varied molecular and phenotypical characteristics. SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes play significant roles in the regulation of gene expression, being essential for processes such as cell maintenance and differentiation in hematopoietic stem cells. Furthermore, alterations in SWI/SNF complex subunits, especially in ARID1A/1B/2, SMARCA2/4, and BCL7A, are highly recurrent across a wide variety of lymphoid and myeloid malignancies. Most genetic alterations cause a loss of function of the subunit, suggesting a tumor suppressor role. However, SWI/SNF subunits can also be required for tumor maintenance or even play an oncogenic role in certain disease contexts. The recurrent alterations of SWI/SNF subunits highlight not only the biological relevance of SWI/SNF complexes in hematological malignancies but also their clinical potential. In particular, increasing evidence has shown that mutations in SWI/SNF complex subunits confer resistance to several antineoplastic agents routinely used for the treatment of hematological malignancies. Furthermore, mutations in SWI/SNF subunits often create synthetic lethality relationships with other SWI/SNF or non-SWI/SNF proteins that could be exploited therapeutically. In conclusion, SWI/SNF complexes are recurrently altered in hematological malignancies and some SWI/SNF subunits may be essential for tumor maintenance. These alterations, as well as their synthetic lethal relationships with SWI/SNF and non-SWI/SNF proteins, may be pharmacologically exploited for the treatment of diverse hematological cancers.

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Altered BAF occupancy and transcription factor dynamics in PBAF-deficient melanoma

Cited by 24 publications

References 95 publications

Application of the 3C Method to Study the Developmental Genes in Drosophila Larvae

Application of the 3C Method to Study the Developmental Genes in Drosophila Larvae

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

SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities

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