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Project description:Cancer cells utilize epigenetic alterations to acquire autonomous capabilities for tumor maintenance. Here, we show that pancreatic ductal adenocarcinoma (PDA) cells utilize super-enhancers (SEs) to activate the transcription factor EVI1 (ecotropic viral integration site 1) gene, resulting in activation of an EVI1-dependent transcription program conferring PDA tumorigenesis. Our data indicate that SE is the vital cis-acting element to maintain aberrant EVI1 transcription in PDA cells. Consistent with disease progression and inferior survival outcomes of PDA patients, we further show that EVI1 upregulation is a major cause of aggressive tumor phenotypes. Specifically, EVI1 promotes anchorage-independent growth and motility in vitro and enhances tumor propagation in vivo. Mechanistically, EVI1-dependent activation of tumor-promoting gene expression programs through the stepwise configuration of the active enhancer chromatin attributes to these phenotypes. In sum, our findings support the premise that EVI1 is a crucial driver of oncogenic transcription programs in PDA cells. Further, we emphasize the instructive role of epigenetic aberrancy in establishing PDA tumorigenesis.
| S-EPMC8210884 | biostudies-literature
Project description:Cancer cells utilize epigenetic alterations to acquire autonomous capabilities for tumor maintenance. Here, we show that pancreatic ductal adenocarcinoma (PDA) cells hijack super-enhancers (SEs) to activate the EVI1 gene with its tumor-intrinsic program. We demonstrate that SE is the vital cis-acting element to maintain aberrant EVI1 transcription in PDA cells. Related to disease progression and inferior survival outcomes in human PDA, functional experiments further show that EVI1 upregulation is the cause of aggressive tumor phenotypes. In particular, EVI1 mediates the resistance to anchorage-independent growth and enhanced motility in vitro, with efficient tumor propagation in vivo. EVI1-dependent activation of gene expression program attributes to these phenotypes, by which EVI1 drives the stepwise configuration of the active enhancer chromatin. In sum, our findings support the promise that EVI1 is a crucial driver of oncogenic transcription program in PDA cells. Further, we emphasize the instructive role of epigenetic aberrancy in establishing PDA tumorigenesis.
2021-05-20 | GSE166510 | GEO
Project description:Cancer cells utilize epigenetic alterations to acquire autonomous capabilities for tumor maintenance. Here, we show that pancreatic ductal adenocarcinoma (PDA) cells hijack super-enhancers (SEs) to activate the EVI1 gene with its tumor-intrinsic program. We demonstrate that SE is the vital cis-acting element to maintain aberrant EVI1 transcription in PDA cells. Related to disease progression and inferior survival outcomes in human PDA, functional experiments further show that EVI1 upregulation is the cause of aggressive tumor phenotypes. In particular, EVI1 mediates the resistance to anchorage-independent growth and enhanced motility in vitro, with efficient tumor propagation in vivo. EVI1-dependent activation of gene expression program attributes to these phenotypes, by which EVI1 drives the stepwise configuration of the active enhancer chromatin. In sum, our findings support the promise that EVI1 is a crucial driver of oncogenic transcription program in PDA cells. Further, we emphasize the instructive role of epigenetic aberrancy in establishing PDA tumorigenesis.
2021-05-20 | GSE166509 | GEO
Project description:Cancer cells utilize epigenetic alterations to acquire autonomous capabilities for tumor maintenance. Here, we show that pancreatic ductal adenocarcinoma (PDA) cells hijack super-enhancers (SEs) to activate the EVI1 gene with its tumor-intrinsic program. We demonstrate that SE is the vital cis-acting element to maintain aberrant EVI1 transcription in PDA cells. Related to disease progression and inferior survival outcomes in human PDA, functional experiments further show that EVI1 upregulation is the cause of aggressive tumor phenotypes. In particular, EVI1 mediates the resistance to anchorage-independent growth and enhanced motility in vitro, with efficient tumor propagation in vivo. EVI1-dependent activation of gene expression program attributes to these phenotypes, by which EVI1 drives the stepwise configuration of the active enhancer chromatin. In sum, our findings support the promise that EVI1 is a crucial driver of oncogenic transcription program in PDA cells. Further, we emphasize the instructive role of epigenetic aberrancy in establishing PDA tumorigenesis.
2021-05-20 | GSE166508 | GEO
Project description:EVI1 activates tumor-promoting transcriptional enhancers in pancreatic cancer.
| PRJNA701163 | ENA
Project description:EVI1 activates tumor-promoting transcriptional enhancers in pancreatic cancer [RNA-seq].
| PRJNA701166 | ENA
Project description:EVI1 activates tumor-promoting transcriptional enhancers in pancreatic cancer [ChIP-seq].
| PRJNA701167 | ENA
Project description:EVI1 activates tumor-promoting transcriptional enhancers in pancreatic cancer [ATAC-seq].
| PRJNA701168 | ENA
Project description:PURPOSE OF REVIEW:Common genetic variants that associate with type 2 diabetes risk are markedly enriched in pancreatic islet transcriptional enhancers. This review discusses current advances in the annotation of islet enhancer variants and their target genes. RECENT FINDINGS:Recent methodological advances now allow genetic and functional mapping of diabetes causal variants at unprecedented resolution. Mapping of enhancer-promoter interactions in human islets has provided a unique appreciation of the complexity of islet gene regulatory processes and enabled direct association of noncoding diabetes risk variants to their target genes. The recently improved human islet enhancer annotations constitute a framework for the interpretation of diabetes genetic signals in the context of pancreatic islet gene regulation. In the future, integration of existing and yet to come regulatory maps with genetic fine-mapping efforts and in-depth functional characterization will foster the discovery of novel diabetes molecular risk mechanisms.
| S-EPMC6872509 | biostudies-literature
Project description:BackgroundThe transcription factor Ecotropic Virus Integration site 1 (EVI1) regulates cellular proliferation, differentiation, and apoptosis, and its overexpression contributes to an aggressive course of disease in myeloid leukemias and other malignancies. Notwithstanding, knowledge about the target genes mediating its biological and pathological functions remains limited. We therefore aimed to identify and characterize novel EVI1 target genes in human myeloid cells.MethodsU937T_EVI1, a human myeloid cell line expressing EVI1 in a tetracycline regulable manner, was subjected to gene expression profiling. qRT-PCR was used to confirm the regulation of membrane-spanning-4-domains subfamily-A member-3 (MS4A3) by EVI1. Reporter constructs containing various parts of the MS4A3 upstream region were employed in luciferase assays, and binding of EVI1 to the MS4A3 promoter was investigated by chromatin immunoprecipitation. U937 derivative cell lines experimentally expressing EVI1 and/or MS4A3 were generated by retroviral transduction, and tested for their tumorigenicity by subcutaneous injection into severe combined immunodeficient mice.ResultsGene expression microarray analysis identified 27 unique genes that were up-regulated, and 29 unique genes that were down-regulated, in response to EVI1 induction in the human myeloid cell line U937T. The most strongly repressed gene was MS4A3, and its down-regulation by EVI1 was confirmed by qRT-PCR in additional, independent experimental model systems. MS4A3 mRNA levels were also negatively correlated with those of EVI1 in several published AML data sets. Reporter gene assays and chromatin immunoprecipitation showed that EVI1 regulated MS4A3 via direct binding to a promoter proximal region. Experimental re-expression of MS4A3 in an EVI1 overexpressing cell line counteracted the tumor promoting effect of EVI1 in a murine xenograft model by increasing the rate of apoptosis.ConclusionsOur data reveal MS4A3 as a novel direct target of EVI1 in human myeloid cells, and show that its repression plays a role in EVI1 mediated tumor aggressiveness.
| S-EPMC4389965 | biostudies-literature