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Pharmacologic inhibition of BAF chromatin remodeling complexes as a therapeutic approach to transcription factor-dependent cancers [ChIP-seq]

ABSTRACT: The BRG/Brahma-associated factors (BAF or mSWI/SNF) family of chromatin remodeling complexes are critical regulators of gene expression and are major determinants of cancer and other diseases. Two paralog ATPases, SMARCA4 and SMARCA2 (BRG1 and BRM, respectively), provide the enzymatic activity required for chromatin remodeling. Here, we discover and characterize a novel series of compounds that potently and selectively inhibit SMARCA4/SMARCA2. Mutational and biochemical studies demonstrate that these inhibitors act through a unique mode of inhibition, distinct from reported SMARCA4/SMARCA2 inhibitors. Across a range of cancer cell lines, SMARCA4/SMARCA2 inhibition resulted in lineage-specific changes in chromatin accessibility at binding sites for key transcription factors (TFs). In uveal melanoma (UM), BAF inhibition resulted in loss of enhancer occupancy of SOX10 and MITF, two essential TFs, leading to down-regulation of the melanocytic gene expression program. In a mouse xenograft model of UM, SMARCA4/SMARCA2 inhibition was well tolerated and resulted in dose-dependent tumor regression correlating with pharmacodynamic modulation of BAF-target gene expression. These data provide the foundation for first-in-human studies of BAF ATPase inhibition as a novel therapeutic to treat TF-dependent cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241446 | GEO | 2023/09/12

REPOSITORIES: GEO

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Pharmacologic inhibition of BAF chromatin remodeling complexes as a therapeutic approach to transcription factor-dependent cancers [ATAC-seq]

Project description:The BRG/Brahma-associated factors (BAF or mSWI/SNF) family of chromatin remodeling complexes are critical regulators of gene expression and are major determinants of cancer and other diseases. Two paralog ATPases, SMARCA4 and SMARCA2 (BRG1 and BRM, respectively), provide the enzymatic activity required for chromatin remodeling. Here, we discover and characterize a novel series of compounds that potently and selectively inhibit SMARCA4/SMARCA2. Mutational and biochemical studies demonstrate that these inhibitors act through a unique mode of inhibition, distinct from reported SMARCA4/SMARCA2 inhibitors. Across a range of cancer cell lines, SMARCA4/SMARCA2 inhibition resulted in lineage-specific changes in chromatin accessibility at binding sites for key transcription factors (TFs). In uveal melanoma (UM), BAF inhibition resulted in loss of enhancer occupancy of SOX10 and MITF, two essential TFs, leading to down-regulation of the melanocytic gene expression program. In a mouse xenograft model of UM, SMARCA4/SMARCA2 inhibition was well tolerated and resulted in dose-dependent tumor regression correlating with pharmacodynamic modulation of BAF-target gene expression. These data provide the foundation for first-in-human studies of BAF ATPase inhibition as a novel therapeutic to treat TF-dependent cancers.

2023-09-11 | GSE241445 | GEO

Pharmacologic inhibition of BAF chromatin remodeling complexes as a therapeutic approach to transcription factor-dependent cancers [PRO-seq]

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Pharmacologic inhibition of BAF chromatin remodeling complexes as a therapeutic approach to transcription factor-dependent cancers [WES]

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Pharmacologic inhibition of BAF chromatin remodeling complexes as a therapeutic approach to transcription factor-dependent cancers [RNA-seq]

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Acute BAF perturbation causes immediate changes in chromatin accessibility

Project description:Loss-of-function mutations in genes coding for subunits of the large, multifarious BRG1/BRM associated factor (BAF) chromatin remodeling complexes are frequently causative for cancer or developmental diseases1-5. Cells lacking the most frequently mutated subunits like the ATPase SMARCA4 typically exhibit drastic chromatin accessibility changes, especially of important regulatory regions6-12. However, so far it remains unknown how these changes are established over time, and whether they are causative for intra-complex synthetic lethalities abrogating the formation (SMARCC1-SMARCC2)8,13,14 or activity (SMARCA4-SMARCA2)15-17 of BAF complexes. Here, we utilize the dTAG system18 to induce acute degradation of BAF subunits in wild-type and BAF mutant backgrounds and analyze the resulting chromatin accessibility changes with high kinetic resolution. We observe that chromatin alterations are established faster than the duration of one cell cycle and that maintaining genome accessibility requires constant ATP-dependent remodeling. Completely abolishing BAF complex function by acute degradation of a synthetic lethal subunit in a paralog-deficient background results in a near-complete loss of chromatin accessibility at BAF-controlled sites, especially at super-enhancers, providing a mechanism for intra-complex synthetic lethalities.

2020-12-23 | PXD018381 | Pride

A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo

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2022-06-20 | PXD032239 | Pride

Gene expression changes in MV4-11 cells upon SMARCA4 knock-down and PFI-3 treatment

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2015-07-12 | E-GEOD-67920 | biostudies-arrayexpress

SMARCA4 Rescue Profiling [Dnase]

Project description:Mutations in SMARCA4, a central ATPase of the human BAF/PBAF chromatin remodeling complexes, cause developmental abnormalities and promote cancer development. The pathogenic effects of SMARCA4 loss are often linked to the de-regulation of a relatively small number of key target genes. Here, to understand how chromatin remodeling by SMARCA4 results in specific transcriptional perturbations, we used genome engineering to correct a homozygous mutation in SMARCA4 in the well-characterized lung adenocarcinoma A549 cell line and profiled changes in SMARCA2/4 occupancy, chromatin accessibility, histone marks and transcription. Restoration of SMARCA4 causes a dramatic increase in chromatin accessibility at low affinity TF binding sites. Despite the widespread increase in chromatin accessibility, we observe comparatively attenuated changes in gene expression. Although there is a marked correlation between the number of local activated DHSs and the transcriptional responsivity of a gene, the influence of distal DHSs appears modified by a gene's promoter architecture and domain-scale chromatin organization. The largest changes in expression occur for genes in isolated, SMARCA4 sensitive chromatin domains that undergo region-wide chromatin remodeling upon reintroduction of SMARCA4. Our results reveal that interactions between distal enhancers, genome organization, and promoter architecture add transcriptional specificity to the global chromatin effects of BAF/PBAF complex perturbation and target the response to key developmental pathways.

2020-05-20 | GSE132292 | GEO

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