Placental co-transcriptional activator Vestigial-like 1 (VGLL1) drives tumorigenesis via increasing transcription of proliferation and invasion genes [ChIP-seq]
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ABSTRACT:
PROVIDER: PRJNA1113182 | ENA |
REPOSITORIES: ENA
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Project description:Vestigial-like 1 (VGLL1) is a co-transcriptional activator that binds to TEA domain-containing transcription factors (TEADs). Its expression is upregulated in a variety of aggressive cancer types, including pancreatic and basal-like breast cancer, and increased transcription of VGLL1 is strongly correlated with poor prognosis and decreased overall patient survival. In normal tissues, VGLL1 is most highly expressed within placental trophoblast cells, which share the common attributes of rapid cellular proliferation and invasion with tumor cells. The impact of VGLL1 in cancer has not been fully elucidated and no VGLL1-targeted therapy currently exists. The aim of this study was to evaluate the cellular function and downstream genomic targets of VGLL1 in placental, pancreatic, and breast cancer cells. Functional assays were employed to assess the role of VGLL1 in cellular invasion and proliferation, and ChIP-seq and RNA-seq assays were performed to identify VGLL1 target genes and potential impact using pathway analysis. ChIP-seq analysis identified eight transcription factors with a VGLL1-binding motif that were common between all three cell types, including TEAD1-4, AP-1, and GATA6, and revealed ~3,000 shared genes with which VGLL1 interacts. Furthermore, increased VGLL1 expression led to an enhancement of cell invasion and proliferation, which was supported by RNA-seq analysis showing transcriptional changes in several genes known to be involved in these processes. This work expands our mechanistic understanding of VGLL1 function in tumor cells and provides a strong rationale for developing VGLL1-targeted therapies for treating cancer patients.
2024-05-25 | GSE267818 | GEO
Project description:Vestigial-like 1 (VGLL1) is a co-transcriptional activator that binds to TEA domain-containing transcription factors (TEADs). Its expression is upregulated in a variety of aggressive cancer types, including pancreatic and basal-like breast cancer, and increased transcription of VGLL1 is strongly correlated with poor prognosis and decreased overall patient survival. In normal tissues, VGLL1 is most highly expressed within placental trophoblast cells, which share the common attributes of rapid cellular proliferation and invasion with tumor cells. The impact of VGLL1 in cancer has not been fully elucidated and no VGLL1-targeted therapy currently exists. The aim of this study was to evaluate the cellular function and downstream genomic targets of VGLL1 in placental, pancreatic, and breast cancer cells. Functional assays were employed to assess the role of VGLL1 in cellular invasion and proliferation, and ChIP-seq and RNA-seq assays were performed to identify VGLL1 target genes and potential impact using pathway analysis. ChIP-seq analysis identified eight transcription factors with a VGLL1-binding motif that were common between all three cell types, including TEAD1-4, AP-1, and GATA6, and revealed ~3,000 shared genes with which VGLL1 interacts. Furthermore, increased VGLL1 expression led to an enhancement of cell invasion and proliferation, which was supported by RNA-seq analysis showing transcriptional changes in several genes known to be involved in these processes. This work expands our mechanistic understanding of VGLL1 function in tumor cells and provides a strong rationale for developing VGLL1-targeted therapies for treating cancer patients.
2024-05-25 | GSE267817 | GEO
Project description:Placental co-transcriptional activator Vestigial-like 1 (VGLL1) drives tumorigenesis via increasing transcription of proliferation and invasion genes [RNA-seq]
| PRJNA1113183 | ENA
Project description:Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regression by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from tumor specimens of 35 PDAC patients. This led to the identification of a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1), a novel putative TAA demonstrating overexpression in multiple tumor types and low or absent transcript expression in essential normal tissues. VGLL1-specific CTLs isolated and expanded from the blood of a male PDAC patient showed the capacity to recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung and basal-like breast cancers. Gene expression profiling revealed that VGLL1 is a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic TAA targets for patients with multiple different cancer types.
2020-10-19 | PXD018302 | Pride
Project description:Placenta abnormality is one of the key reasons for early pregnancy loss but the regulatory mechanisms underlying placenta formation are largely unknown. Here, we applied a human naïve pluripotent stem cell (PSC) derived TE model to explore the driven regulatory machinery. We demonstrate that VGLL1 (vestigial like family member 1) is crucial for TE self-renewal and TE-specific gene expression, thus suppressing VGLL1 leads to severely impaired cell proliferation and skewed TE induction. VGLL1 exerts its function through interacting with TEAD4 (TEA domain transcription factor 4) and colocalize at target gene promoters and enhancers. Further investigation uncovers the enrichment of H3K27ac active histone marks at genomic regions occupied by VGLL1-TEAD4 complex, indicates a close association between them. Overall, our data reveals the critical function model of VGLL1-TEAD4 in human TE derivation, highlighting a potential interspecies difference between human and mouse TE induction.
2023-12-18 | GSE193619 | GEO
Project description:Placenta abnormality is one of the key reasons for early pregnancy loss but the regulatory mechanisms underlying placenta formation are largely unknown. Here, we applied a human naïve pluripotent stem cell (PSC) derived TE model to explore the driven regulatory machinery. We demonstrate that VGLL1 (vestigial like family member 1) is crucial for TE self-renewal and TE-specific gene expression, thus suppressing VGLL1 leads to severely impaired cell proliferation and skewed TE induction. VGLL1 exerts its function through interacting with TEAD4 (TEA domain transcription factor 4) and colocalize at target gene promoters and enhancers. Further investigation uncovers the enrichment of H3K27ac active histone marks at genomic regions occupied by VGLL1-TEAD4 complex, indicates a close association between them. Overall, our data reveals the critical function model of VGLL1-TEAD4 in human TE derivation, highlighting a potential interspecies difference between human and mouse TE induction.
2023-12-18 | GSE193618 | GEO
Project description:Placenta abnormality is one of the key reasons for early pregnancy loss but the regulatory mechanisms underlying placenta formation are largely unknown. Here, we applied a human naïve pluripotent stem cell (PSC) derived TE model to explore the driven regulatory machinery. We demonstrate that VGLL1 (vestigial like family member 1) is crucial for TE self-renewal and TE-specific gene expression, thus suppressing VGLL1 leads to severely impaired cell proliferation and skewed TE induction. VGLL1 exerts its function through interacting with TEAD4 (TEA domain transcription factor 4) and colocalize at target gene promoters and enhancers. Further investigation uncovers the enrichment of H3K27ac active histone marks at genomic regions occupied by VGLL1-TEAD4 complex, indicates a close association between them. Overall, our data reveals the critical function model of VGLL1-TEAD4 in human TE derivation, highlighting a potential interspecies difference between human and mouse TE induction.
2023-12-18 | GSE193612 | GEO
Project description:In contrast to rodents, the mechanisms underlying human trophectoderm and early placenta specification are understudied due to ethical barriers and the scarcity of embryos. Recent reports have shown that human pluripotent stem cells (PSCs) can differentiate into trophectoderm (TE)-like cells (TELCs) and trophoblast stem cells (TSCs), offering a valuable in vitro model to study early placenta specification. Here, we demonstrate that the VGLL1 (vestigial-likefamilymember1), which is highly expressed during human and non-human primate TE specification in vivo but is negligibly expressed in mouse, is a critical regulator of cell fate determination and self-renewal in human TELCs and TSCs derived from naïve PSCs. Mechanistically, VGLL1 partners with the transcription factor TEAD4 (TEA domain transcription factor 4) to regulate chromatin accessibility at target gene loci through histone acetylation and acts in cooperation with GATA3 and TFAP2C. Our work is relevant to understand primate early embryogenesis and how it differs from other mammalian species.
2024-01-05 | GSE252377 | GEO
Project description:To investigate the function of VGLL1 in breast cancer and its role in the resistance to endocrine therapies we generated stable MCF7 cells overexpressing VGLL1 using CRISPR/Cas9 Synergistic Activation Mediator (SAM) method (MCF7 ActCas9-VGLL1 cells). MCF7 ActCas9-VGLL1 cells were also cultured in the presence of fulvestrant 100nmM or 1µM to develop fulvestrant resistant cells (MCF7 ActCas9-VGLL1-FULVR) and RNA-seq was performed in the different cell lines.
2023-12-05 | GSE216528 | GEO