CoREST Complex Inhibition Alters RNA Splicing to Promote Neoantigen Expression and Enhance Tumor Immunity [PRO-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1178620 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31136202_1.fastq.gz | Fastqsanger.gz | |||
| SRR31136202_2.fastq.gz | Fastqsanger.gz | |||
| SRR31136203_1.fastq.gz | Fastqsanger.gz | |||
| SRR31136203_2.fastq.gz | Fastqsanger.gz | |||
| SRR31136204_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
Similar Datasets
Project description:Epigenetic macromolecular enzyme complexes tightly regulate gene expression at the chromatin level and have recently been found to colocalize with RNA splicing machinery during active transcription1; however, the precise functional consequences of these interactions are uncertain. Here, we identify unique interactions of the CoREST repressor complex (LSD1-HDAC1-CoREST) with components of the RNA splicing machinery and their functional consequences in tumorigenesis. Using mass spectrometry, in vivo binding assays, and cryo-EM we find that CoREST complex-splicing factor interactions are direct and perturbed by the CoREST complex selective inhibitor, corin2–5, leading to extensive changes in RNA splicing in melanoma and other malignancies. Moreover, these corin-induced splicing changes are shown to promote global effects on oncogenic and survival-associated splice variants leading to a tumor-suppressive phenotype. Using predictive machine learning models, MHC IP-MS, and ELISpot assays we identify thousands of neopeptides derived from unannotated splice sites which generate corin-induced splice neoantigens that are demonstrated to be immunogenic in vitro. Corin is further shown to reactivate the response to immune checkpoint blockade and promote dramatic expansion of cytotoxic T cells in an immune cold melanoma tumor model, effectively sensitizing them to anti-PD1 immunotherapy. These data position CoREST complex inhibition as a unique therapeutic opportunity in cancer which perturbs oncogenic splicing programs across broad tumor types while also creating tumor-associated neoantigens that enhance the immunogenicity of current therapeutics and may be readily translated to the clinic.
2025-05-31 | GSE280448 | GEO
Project description:Immunopeptidome analysis in support of the manuscript "CoREST Inhibition Alters RNA Splicing to Promote Neoantigen Expression and Enhance Tumor Immunity"
2024-10-13 | MSV000096071 | MassIVE
Project description:CoREST Complex Inhibition Alters RNA Splicing to Promote Neoantigen Expression and Enhance Tumor Immunity [scRNA-seq]
| PRJNA1178621 | ENA
Project description:CoREST Complex Inhibition Alters RNA Splicing to Promote Neoantigen Expression and Enhance Tumor Immunity [RNA-seq]
| PRJNA1178617 | ENA
Project description:Epigenetic mechanisms tightly regulate gene expression at the chromatin level and have recently been found to colocalize with the splicing machinery during active transcription; however, the precise functional consequences of these interactions are uncertain. Here, we identify unique interactions of the CoREST repressor complex with the RNA splicing machinery and their functional consequences. Using mass spectrometry, in vivo binding assays, and Cryo-EM we find that CoREST-splicing factor interactions are direct and perturbed by the bivalent inhibitor, corin, leading to robust changes in RNA splicing in melanoma and other malignancies. Moreover, these corin-associated splicing changes are shown to promote global effects on oncogenic and survival-associated splice variants leading to a tumor-suppressive phenotype. Using predictive machine learning models, MHC IP-MS, and ELISpot assays we identify thousands of neopeptides derived from unannotated splice sites which generate corin-induced splice neoantigens that are demonstrated to be immunogenic in vitro. Corin is further shown to inhibit tumor growth and enhance checkpoint blockade in a manner dependent on host T cells that trigger an anti-tumor T cell response in vivo and promote dramatic expansion of cytotoxic T cells in an immune cold melanoma tumor model, effectively sensitizing them to anti-PD1 immunotherapy. These data position CoREST inhibition as a unique therapeutic opportunity in cancer which reverses oncogenic splicing programs across broad tumor types while also creating tumor-associated neoantigens which may enhance the immunogenicity of current therapeutics and may be readily translated to the clinic.
2025-11-10 | PXD056700 | Pride
Project description:Epigenetic macromolecular enzyme complexes tightly regulate gene expression at the chromatin level and have recently been found to colocalize with RNA splicing machinery during active transcription1; however, the precise functional consequences of these interactions are uncertain. Here, we identify unique interactions of the CoREST repressor complex (LSD1-HDAC1-CoREST) with components of the RNA splicing machinery and their functional consequences in tumorigenesis. Using mass spectrometry, in vivo binding assays, and cryo-EM we find that CoREST complex-splicing factor interactions are direct and perturbed by the CoREST complex selective inhibitor, corin2–5, leading to extensive changes in RNA splicing in melanoma and other malignancies. Moreover, these corin-induced splicing changes are shown to promote global effects on oncogenic and survival-associated splice variants leading to a tumor-suppressive phenotype. Using predictive machine learning models, MHC IP-MS, and ELISpot assays we identify thousands of neopeptides derived from unannotated splice sites which generate corin-induced splice neoantigens that are demonstrated to be immunogenic in vitro. Corin is further shown to reactivate the response to immune checkpoint blockade and promote dramatic expansion of cytotoxic T cells in an immune cold melanoma tumor model, effectively sensitizing them to anti-PD1 immunotherapy. These data position CoREST complex inhibition as a unique therapeutic opportunity in cancer which perturbs oncogenic splicing programs across broad tumor types while also creating tumor-associated neoantigens that enhance the immunogenicity of current therapeutics and may be readily translated to the clinic.
2025-05-31 | GSE280449 | GEO
Project description:Epigenetic macromolecular enzyme complexes tightly regulate gene expression at the chromatin level and have recently been found to colocalize with RNA splicing machinery during active transcription1; however, the precise functional consequences of these interactions are uncertain. Here, we identify unique interactions of the CoREST repressor complex (LSD1-HDAC1-CoREST) with components of the RNA splicing machinery and their functional consequences in tumorigenesis. Using mass spectrometry, in vivo binding assays, and cryo-EM we find that CoREST complex-splicing factor interactions are direct and perturbed by the CoREST complex selective inhibitor, corin2–5, leading to extensive changes in RNA splicing in melanoma and other malignancies. Moreover, these corin-induced splicing changes are shown to promote global effects on oncogenic and survival-associated splice variants leading to a tumor-suppressive phenotype. Using predictive machine learning models, MHC IP-MS, and ELISpot assays we identify thousands of neopeptides derived from unannotated splice sites which generate corin-induced splice neoantigens that are demonstrated to be immunogenic in vitro. Corin is further shown to reactivate the response to immune checkpoint blockade and promote dramatic expansion of cytotoxic T cells in an immune cold melanoma tumor model, effectively sensitizing them to anti-PD1 immunotherapy. These data position CoREST complex inhibition as a unique therapeutic opportunity in cancer which perturbs oncogenic splicing programs across broad tumor types while also creating tumor-associated neoantigens that enhance the immunogenicity of current therapeutics and may be readily translated to the clinic.
2025-05-31 | GSE280450 | GEO
Project description:Pro-inflammatory diet exacerbates colitis and alters gut microbiota
| PRJNA921895 | ENA
Project description:Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.
2023-12-01 | GSE248401 | GEO
Project description:Microbial systems have been synthetically engineered to deploy therapeutic payloads in vivo. With emerging evidence that bacteria naturally home to tumors and modulate anti-tumor immunity one promising application is the development of bacterial vectors as precision cancer vaccines. In this study, we engineered probiotic E. coli Nissle 1917 (EcN) as an anti-tumor vaccination platform optimized for enhanced production and cytosolic delivery of neoepitope-containing peptide arrays, with increased susceptibility to blood clearance and phagocytosis. These features enhance both safety and immunogenicity, achieving a system which drives potent and specific T cell–mediated anti‑cancer immunity that effectively controls or eliminates tumor growth and extends survival in advanced murine primary and metastatic solid tumors. We demonstrate that the elicited anti-tumor immune response involves extensive priming and activation of neoantigen-specific CD4+ and CD8+ T cells, broader activation of both T and NK cells, and a reduction of tumor-infiltrating immunosuppressive myeloid and regulatory T and B cell populations. Taken together, this work leverages the advantages of living medicines to deliver arrays of tumor‑specific neoantigen–derived epitopes within the optimal context to induce specific, effective, and durable systemic anti-tumor immunity.
2024-07-21 | GSE244808 | GEO