Single-cell analysis of mesenteric lymphatic endothelial cells following lymphatic-specific deletion of ERG/FLI1
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PROVIDER: PRJNA1258171 | ENA |
REPOSITORIES: ENA
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Project description:To investigate the transcriptomic changes following dual deletion of transcription factors ERG and FLI1, lymphatic endothelial cells (LEC) from mesenteries of WT or double deleted mice were FACS sorted and single-cell RNA seq was performed.
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Project description:ERG and FLI1 are important regulators of angiogenesis, but their role in lymphatic vasculature is less known. The goal of this study was to determine the role of ERG and FLI1 in postnatal lymphangiogenesis and their involvement in SSc lymphatic system defects. IF were used to detect ERG and FLI1 in SSc and healthy controls (HC) skin biopsies. Human lymphatic endothelial cells (LECs) were used in cell culture experiments. Transcriptional and chromatin analysis of ERG or FLI1 silenced LECs was performed using microarrays and ATAC-seq, respectively. Effects of ERG and FLI1 deficiency on in vitro tubulogenesis was examined using Matrigel assay. Erg and Fli1 endothelial specific knockouts (ErgCKO and Fli1CKO) and lymphatic specific knockouts (ProxErgCKO and ProxFli1CKO) were generated to examine vessel regeneration. ERG and FLI1 protein levels were reduced in blood and lymphatic vasculature in SSc skin biopsies. ERG and FLI1 were shown to regulate genes involved in lymphatic vessel specification, including VEGFR3/FLT4, LYVE-1, and PROX1, and this effect was, at least in part, due to chromatin remodeling. ERG/FLT4 pathway regulated in vitro tubulogenesis in LECs. Deficiency of Erg and Fli1 impaired function of blood and lymphatic vessel during wound healing. ERG and FLI1 are essential regulators of blood and lymphatic vessel regeneration. Deficiency of ERG and FLI1 in SSc endothelial cells, may contribute to rarefaction of blood and lymphatic vasculature in SSc patients. Microarray analysis was performed at The Boston University Microarray Core Facility. Affymetrix CEL files were normalized to produce gene-level expression values using the implementation of the Robust Multiarray Average (RMA) in the affy package (version 1.36.1) included within in the Bioconductor software suite (version 2.12) and an Entrez Gene-specific probe set mapping from BrainArray (version 16.0.0). RLE and NUSE quality metrics were computed using the affy PLM Bioconductor package (version 1.34.0). All microarray analyses were performed using the R environment for statistical computing (version 2.15.1).
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Project description:ERG and FLI1 were silenced in HPAECs using siRNA for 48h.
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Project description:ERG and FLI1 in endothelial cells
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Project description:Deficiency of lymphatic ERG and FLI1 in systemic sclerosis is associated with rarefaction of skin blood and lymphatic vasculature
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Project description:Endothelial-to-mesenchymal transition (EndMT) in which endothelial cells lose their characteristics and acquire mesenchymal property has recently been recognized as a driver of disease progression in wide range of pathologies. However, the regulatory mechanism of EndMT has not been fully understood. Here, we found that combined knockdown of two ETS family transcription factors, ERG and FLI1, induced EndMT. Hence, we analyzed functions of ERG and FLI1 using gene expression microarray and ChIP-seq to elucidate the regulatory mechanism of EndMT.
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Project description:The goal and objective of this study was to identify the transcriptional profiles differentiating the artery, vein, and lymphatic lineages in the adult rat vasculature with particular emphasis on the unique elements of the collecting lymphatic vessel transcriptome. A 2 x 3 experimental design was utilized in which parallel arteries, veins, and lymphatics from two different tissue beds were examined. The rat thoracic duct was selected as a large, post-nodal collecting lymphatic vessel that exhibits excellent conduit-type behavior while the rat mesenteric lymphatic was selected as a smaller, pre-nodal collecting lymphatic vessel that exhibits excellent pump behavior (see Gashev AA, et al. Microcirculation. 2004 Sep;11(6):477-92. [PMID: 15371129]). The axillary artery and vein were selected for comparison to the thoracic duct due to their similar anatomical position distal to the common junction of the lymphatic and venous vascular trees and represent a large artery and large vein, respectively. The mesentery artery and vein were selected for comparison to the mesenteric lymphatic vessels due to their parallel position within the mesenteric vasculature and represent a small atery and small vein, respectively. A 2 x 3, reference-based, experimental design was utilized consisting of both large (thoracic) and small (mesenteric) arteries, veins, and collecting lymphatic vessels for a total of 6 sample groups with n=6 biological replicates present in each group. All vessels acquired from the same donor animal have the same numerical label and were handled in parallel through all experimental steps. Each vessel sample RNA sample was amplified, labeled with Cy5, and compared to the same Rat Universal Reference RNA sample (Stratagene, La Jolla, CA) that was amplified and labeled with Cy3 dye. No dye swaps were utilized.
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Project description:Ewing sarcomas harbor few mutations beyond the chromosomal translocation that initiates disease and the mechanistic basis for the metastasis of these tumors remains poorly understood. The epigenome of Ewing sarcoma (EWS) cells reflects the regulatory state of genes associated with the DNA binding activity of the fusion oncoproteins EWSR1::FLI1 or EWSR1::ERG. In this study, we examined the repressive activities of the EWSR1::FLI1/ERG fusion oncoproteins. Focusing on one of the repressed EWSR1::FLI1/ERG target genes, ETS1, we detected EWSR1::FLI1 binding and a H3K27me3 repressive mark at this locus. Depletion of EWSR1::FLI1 results in ETS1’s binding of promoter regions, and we show ETS1 regulates the expression of multiple proteins that function in extracellular matrix organization including TENSIN3 (TSN3). Interestingly, TSN3 expression in EWS tumors significantly correlates with that of ETS1 (0.85, FDR <0.01). TNS3 is a focal adhesion protein that contributes to tumor cell migration by connecting the cytoplasmic tail of integrins to the actin cytoskeleton. EWS cell lines, in which we activated ETS1 expression (CRISPRa) exhibited increased TNS3 expression and a migratory phenotype. Critically, the activated ETS1 EWS cell lines show TNS3 accumulation at leading cell edges, with F-actin cytoskeletal reorganization, a phenotype associated with cell migration.
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Project description:Ewing sarcomas harbor few mutations beyond the chromosomal translocation that initiates disease and the mechanistic basis for the metastasis of these tumors remains poorly understood. The epigenome of Ewing sarcoma (EWS) cells reflects the regulatory state of genes associated with the DNA binding activity of the fusion oncoproteins EWSR1::FLI1 or EWSR1::ERG. In this study, we examined the repressive activities of the EWSR1::FLI1/ERG fusion oncoproteins. Focusing on one of the repressed EWSR1::FLI1/ERG target genes, ETS1, we detected EWSR1::FLI1 binding and a H3K27me3 repressive mark at this locus. Depletion of EWSR1::FLI1 results in ETS1’s binding of promoter regions, and we show ETS1 regulates the expression of multiple proteins that function in extracellular matrix organization including TENSIN3 (TSN3). Interestingly, TSN3 expression in EWS tumors significantly correlates with that of ETS1 (0.85, FDR <0.01). TNS3 is a focal adhesion protein that contributes to tumor cell migration by connecting the cytoplasmic tail of integrins to the actin cytoskeleton. EWS cell lines, in which we activated ETS1 expression (CRISPRa) exhibited increased TNS3 expression and a migratory phenotype. Critically, the activated ETS1 EWS cell lines show TNS3 accumulation at leading cell edges, with F-actin cytoskeletal reorganization, a phenotype associated with cell migration.
2024-04-15 | GSE243279 | GEO
Project description:Ewing sarcomas harbor few mutations beyond the chromosomal translocation that initiates disease and the mechanistic basis for the metastasis of these tumors remains poorly understood. The epigenome of Ewing sarcoma (EWS) cells reflects the regulatory state of genes associated with the DNA binding activity of the fusion oncoproteins EWSR1::FLI1 or EWSR1::ERG. In this study, we examined the repressive activities of the EWSR1::FLI1/ERG fusion oncoproteins. Focusing on one of the repressed EWSR1::FLI1/ERG target genes, ETS1, we detected EWSR1::FLI1 binding and a H3K27me3 repressive mark at this locus. Depletion of EWSR1::FLI1 results in ETS1’s binding of promoter regions, and we show ETS1 regulates the expression of multiple proteins that function in extracellular matrix organization including TENSIN3 (TSN3). Interestingly, TSN3 expression in EWS tumors significantly correlates with that of ETS1 (0.85, FDR <0.01). TNS3 is a focal adhesion protein that contributes to tumor cell migration by connecting the cytoplasmic tail of integrins to the actin cytoskeleton. EWS cell lines, in which we activated ETS1 expression (CRISPRa) exhibited increased TNS3 expression and a migratory phenotype. Critically, the activated ETS1 EWS cell lines show TNS3 accumulation at leading cell edges, with F-actin cytoskeletal reorganization, a phenotype associated with cell migration.
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