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Cancer-specific retargeting of BAF complexes by a prion-like domain [ATAC-Seq]

ABSTRACT: Alterations in the function of transcriptional regulators can orchestrate oncogenic programs that are critical for the transformation and survival of cancer cells. Here we show that the BAF chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of the FET family of proteins containing prion-like domains that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, characterized by the EWS-FLI1 fusion, we find that the BAF complex is recruited by EWS-FLI1 to tumor specific enhancers at GGAA microsatellite repeats and contributes to the activation of target genes. This process depends on tyrosine residues that are necessary for the aggregation properties of the EWSR1 prion-like domain and is a neomorphic feature of EWS-FLI1 compared to the wild type ETS transcription factor FLI1. Furthermore, fusion of short fragments of the EWSR1 prion-like domain to FLI1 is sufficient to recapitulate EWS-FLI1-mediated gene expression. Our studies demonstrate that the aggregation properties of prion-like domains can retarget chromatin regulatory complexes to establish and maintain oncogenic gene expression and proliferation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94272 | GEO | 2017/08/24

SECONDARY ACCESSION(S): PRJNA369230

REPOSITORIES: GEO

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Cancer-specific retargeting of BAF complexes by a prion-like domain [RNA-Seq]

Project description:Alterations in the function of transcriptional regulators can orchestrate oncogenic programs that are critical for the transformation and survival of cancer cells. Here we show that the BAF chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of the FET family of proteins containing prion-like domains that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, characterized by the EWS-FLI1 fusion, we find that the BAF complex is recruited by EWS-FLI1 to tumor specific enhancers at GGAA microsatellite repeats and contributes to the activation of target genes. This process depends on tyrosine residues that are necessary for the aggregation properties of the EWSR1 prion-like domain and is a neomorphic feature of EWS-FLI1 compared to the wild type ETS transcription factor FLI1. Furthermore, fusion of short fragments of the EWSR1 prion-like domain to FLI1 is sufficient to recapitulate EWS-FLI1-mediated gene expression. Our studies demonstrate that the aggregation properties of prion-like domains can retarget chromatin regulatory complexes to establish and maintain oncogenic gene expression and proliferation.

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Oncofusion driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1 [enhancer knockdown]

Project description:Ewing Sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1-ETS (EWS-FLI1/EWSR1-ERG) transcription factors drive EwS by orchestrating an oncogenic transcription program through de novo enhancers. Pharmacological targeting of these oncofusions has been challenged by unstructured prion-like domains and common DNA binding motifs in the EWSR1 and ETS protein, respectively. Alternatively, identification and characterization of mediators and downstream targets of EWS-FLI1 dependent or independent function could offer novel therapeutic options. By integrative analysis of thousands of transcriptome datasets representing pan-cancer cell lines, primary cancer, metastasis, and normal tissues, we have identified a 32 gene signature (ESS32) that could stratify EwS from pan-cancer. Of the ESS32 (Ewing Sarcoma Specific 32), LOXHD1 - coding for a stereociliary protein was the most exquisite gene expressed in EwS. CRISPR-Cas9 mediated deletion or silencing of EWS-FLI1 bound upstream de novo enhancer elements in EwS cells led to the loss of LOXHD1 expression and altered the EWS-FLI1, MYC, and HIF1 pathway genes, resulting in decreased proliferation and invasion in vitro and in vivo. These observations open up new avenues for developing LOXHD1-targeted drugs or cellular therapies for this deadly disease.

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Therapeutic Targeting Ewing Sarcoma through Inhibition of the FACT Complex (RNA-Seq I)

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Tumor-specific retargeting of an oncogenic transcription factor chimera results in dysregulation of chromatin and transcription

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Project description:There is a long-established connection between epigenetic reprogramming and the local function of the spliceosome. Recently the oncogenic potential of this connection has also been recognized. Recent work has demonstrated that EWS-FLI1 recruits the BRG1/BRM-associated factor (BAF) complex, however, the specific BAF subunits that interact with EWS-FLI1 and the role of the BAF complex in oncogenesis remains unknown. Within the BAF complex, the AT-rich interactive domain-containing protein 1A (ARID1A, BAF250a) gene encodes a central scaffold. EWS-FLI1 is a well-described transcriptional regulator that also has a role in modulating RNA splicing. While EWS-FLI1 alters the splicing of many mRNA isoforms, the role of splicing modulation in ES oncogenesis remains unknown. Here we report a direct connection between the EWS-FLI1-induced transcriptome and the EWS-FLI1 protein interactome to reveal a novel interaction with a specific isoform of ARID1A that has a direct impact on oncogenicity. We report a novel feed-forward cycle of EWS-FLI1 and ARID1A-L facilitating ES growth through splicing modulation and protein stability that may lead to improved cancer-specific drug targeting.

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