Correlating Global Gene Regulation to Angiogenesis in the Developing Chick Extra-Embryonic Vascular System

International audienceBACKGROUND: Formation of blood vessels requires the concerted regulation of an unknown number of genes in a spatial-, time- and dosage-dependent manner. Determining genes, which drive vascular maturation is crucial for the identification of new therapeutic targets against pathological angiogenesis. METHOLOGY/PRINCIPAL FINDINGS: We accessed global gene regulation throughout maturation of the chick chorio-allantoic membrane (CAM), a highly vascularized tissue, using pan genomic microarrays. Seven percent of analyzed genes showed a significant change in expression (>2-fold, FDR<5%) with a peak occurring from E7 to E10, when key morphogenetic and angiogenic genes such as BMP4, SMO, HOXA3, EPAS1 and FGFR2 were upregulated, reflecting the state of an activated endothelium. At later stages, a general decrease in gene expression occurs, including genes encoding mitotic factors or angiogenic mediators such as CYR61, EPAS1, MDK and MYC. We identified putative human orthologs for 77% of significantly regulated genes and determined endothelial cell enrichment for 20% of the orthologs in silico. Vascular expression of several genes including ENC1, FSTL1, JAM2, LDB2, LIMS1, PARVB, PDE3A, PRCP, PTRF and ST6GAL1 was demonstrated by in situ hybridization. Up to 9% of the CAM genes were also overexpressed in human organs with related functions, such as placenta and lung or the thyroid. 21-66% of CAM genes enriched in endothelial cells were deregulated in several human cancer types (P<.0001). Interfering with PARVB (encoding parvin, beta) function profoundly changed human endothelial cell shape, motility and tubulogenesis, suggesting an important role of this gene in the angiogenic process. CONCLUSIONS/SIGNIFICANCE: Our study underlines the complexity of gene regulation in a highly vascularized organ during development. We identified a restricted number of novel genes enriched in the endothelium of different species and tissues, which may play crucial roles in normal and pathological angiogenesis

Regulation of PLAGL1 expression in sarcomas

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Regulation of PLAGL1 expression in sarcomas

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Etude de la régulation de l'expression de PLAGL1 dans les sarcomes

Non fourniNon fourniBORDEAUX2-Bib. électronique (335229905) / SudocSudocFranceF

Prognostic Value of <i>PLAGL1</i>-Specific CpG Site Methylation in Soft-Tissue Sarcomas

<div><p>Soft tissue sarcomas (STS) are rare, complex tumors with a poor prognosis. The identification of new prognostic biomarkers is needed to improve patient management. Our aim was to determine the methylation status of the 118 CpG sites in the <i>PLAGL1</i> tumor-suppressor gene P1 CpG island promoter and study the potential prognostic impact of <i>PLAGL1</i> promoter methylation CpG sites in STS. Training cohorts constituted of 28 undifferentiated sarcomas (US) and 35 leiomyosarcomas (LMS) were studied. <i>PLAGL1</i> mRNA expression was investigated by microarray analysis and validated by RT-qPCR. Pyrosequencing was used to analyze quantitative methylation of the <i>PLAGL1</i> promoter. Associations between global promoter or specific CpG site methylation and mRNA expression were evaluated using Pearson’s product moment correlation coefficient. Cox univariate and multivariate proportional hazard models were used to assess the predictive power of CpG site methylation status. Sixteen CpG sites associated with <i>PLAGL1</i> mRNA expression were identified in US and 6 in LMS. Statistical analyses revealed an association between CpG107 methylation status and both overall and metastasis-free survival in US, which was confirmed in a validation cohort of 37 US. The exhaustive study of P1 <i>PLAGL1</i> promoter methylation identified a specific CpG site methylation correlated with mRNA expression, which was predictive for both metastasis-free and overall survival and may constitute the first US-specific biomarker. Such a biomarker may be relevant for identifying patients likely to derive greater benefit from treatment. </p> </div

Pearson’s correlation between <i>PLAGL1</i> mRNA expression and the methylation percentage of CpGs in US and LMS.

<p>Correlation between <i>PLAGL1</i> mRNA expression and the mean methylation percentage of all CpG sites in undifferentiated sarcomas (US) (<b>Aa</b>) and leiomyosarcomas (LMS) (<b>Ba</b>). <b>Ab</b>: Correlation between <i>PLAGL1</i> mRNA expression and the mean methylation percentage of CpGs exhibiting positive correlation with <i>PLAGL1</i> mRNA expression in US. <b>Ac</b>: Correlation between <i>PLAGL1</i> mRNA expression and the mean methylation percentage of CpGs exhibiting negative correlation with <i>PLAGL1</i> mRNA expression in US; <b>Bb</b>: Correlation between <i>PLAGL1</i> mRNA expression and the mean methylation percentage of CpGs exhibiting negative correlation with <i>PLAGL1</i> mRNA expression in LMS. <i>PLAGL1</i> mRNA expression was evaluated by microarray (mean of the 3 Affimetrix probes) and plotted in log2. <i>P</i> ≤ 0.05 are considered significant.</p