Heterozygous mutations in SMARCA2 lead to impaired neurogenesis due to global retargeting of SMARCA4
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE122631 | GEO | 2019/07/30
REPOSITORIES: GEO
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Project description:We generated a library of Smarca4 variants with mutations in conserved regions of the N-terminal ATPase domain based on mutants observed in primary tumors and cancer cell lines. Heterozygous expression of Smarca4 ATPase mutants led to decreased accessibility at active enhancers in mouse embryonic stem cells.
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Project description:SMARCA2 and SMARCA4 are two mutually exclusive ATPase subunits of SWI/SNF complex. SMARCA4 deficient lung cancer population selectively depend on SMARCA2 for cancer growth phenotype. Rescue experiments with ectopic expression of wild-type, bromodomain mutant and ATPase dead SMARCA2 and SMARCA4 highlight that ATPase domain is the drug target. In this study, we performed genome-wide microarray and differential gene expression profiling on isogenic lung cancer lines expressing cDNA rescue constructs for wild-type, bromodomain mutant and ATPase dead SMARCA2 and SMARCA4
2015-07-21 | GSE69088 | GEO
Project description:Lung cancer is the top cause of cancer mortality. Despite recent advances, the majority of patients with lung cancer still lack effective therapeutic options, underscoring the dire need for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. Recent reports have identified the paralogue SMARCA2 to be synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. To overcome this hurdle, we have utilized iterative structure-activity relationship (SAR) studies to develop novel, potent and selective SMARCA2 degrading small molecules based on proteolysis targeting chimera (PROTAC) technology. We demonstrated that YD23, our lead SMARCA2 PROTAC, potently and selectively induces degradation of SMARCA2. Mechanistically, we show that SMARCA2 degradation in SMARCA4-mutant cells induces a profound reprograming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified nuclear effectors of the Hippo pathway, YAP/TEAD, as key co-conspirators of SMARCA2 in driving the growth of SMARCA4-mutant cancer cells that can be disrupted by our degrader. Finally, we show that YD23 has a potent tumor growth inhibitory activity in SMARCA4-mutant xenograft tumors. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against SMARCA4 mutant tumors.
2024-09-27 | GSE236589 | GEO
Project description:Lung cancer is the top cause of cancer mortality. Despite recent advances, the majority of patients with lung cancer still lack effective therapeutic options, underscoring the dire need for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. Recent reports have identified the paralogue SMARCA2 to be synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. To overcome this hurdle, we have utilized iterative structure-activity relationship (SAR) studies to develop novel, potent and selective SMARCA2 degrading small molecules based on proteolysis targeting chimera (PROTAC) technology. We demonstrated that YD23, our lead SMARCA2 PROTAC, potently and selectively induces degradation of SMARCA2. Mechanistically, we show that SMARCA2 degradation in SMARCA4-mutant cells induces a profound reprograming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified nuclear effectors of the Hippo pathway, YAP/TEAD, as key co-conspirators of SMARCA2 in driving the growth of SMARCA4-mutant cancer cells that can be disrupted by our degrader. Finally, we show that YD23 has a potent tumor growth inhibitory activity in SMARCA4-mutant xenograft tumors. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against SMARCA4 mutant tumors.
2024-09-27 | GSE236588 | GEO
Project description:Lung cancer is the top cause of cancer mortality. Despite recent advances, the majority of patients with lung cancer still lack effective therapeutic options, underscoring the dire need for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. Recent reports have identified the paralogue SMARCA2 to be synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. To overcome this hurdle, we have utilized iterative structure-activity relationship (SAR) studies to develop novel, potent and selective SMARCA2 degrading small molecules based on proteolysis targeting chimera (PROTAC) technology. We demonstrated that YD23, our lead SMARCA2 PROTAC, potently and selectively induces degradation of SMARCA2. Mechanistically, we show that SMARCA2 degradation in SMARCA4-mutant cells induces a profound reprograming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified nuclear effectors of the Hippo pathway, YAP/TEAD, as key co-conspirators of SMARCA2 in driving the growth of SMARCA4-mutant cancer cells that can be disrupted by our degrader. Finally, we show that YD23 has a potent tumor growth inhibitory activity in SMARCA4-mutant xenograft tumors. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against SMARCA4 mutant tumors.
2024-09-27 | GSE236587 | GEO
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
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 | GSE132290 | GEO
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
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 | GSE132291 | GEO
Project description:Perturbations to mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complexes have been widely implicated as driving events across cancers1. One such perturbation is the dual loss of the SMARCA4 and SMARCA2 ATPase subunits, which has recently been implicated in rare cancers such as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)2-5, SMARCA4-deficient thoracic sarcomas6 and dedifferentiated endometrial carcinomas7. The consequences of SMARCA4/2 dual loss on the biochemical composition of the complex, chromatin targeting and remodeling capabilities, and subcomplex identity (BAF vs. PBAF) in these cancers are unknown. Here, we leverage SCCOHT cell lines to identify an unexpected ATPase module of mSWI/SNF subunits. Using biochemical and genome-wide profiling assays, we found that the incorporation of the ATPase module is a critical step in the functional specification of BAF and PBAF subcomplexes. Furthermore, by utilizing ATPase mutant variants, we found that the ATPase module mediates two separate and concurrent mSWI/SNF targeting mechanisms, evenly split between catalytically-independent targeting to primed enhancers/promoters and catalytically-dependent targeting to de novo enhancers. Finally, by linking these distinct sites to separate tumor-suppressive gene expression programs across ovarian tissues , we clarify the mechanistic consequences of SMARCA4/2 loss dual loss in these rare tumors.
2019-03-11 | GSE117301 | GEO