Abstract
Vascular endothelial growth factor (VEGF-A) is an important gene in many diseases, such as cancer and cardiovascular diseases. We investigated changes in genome-wide gene expression patterns in murine endothelial cells when the expression of VEGF-A was epigenetically modulated using promoter targeted small hairpin RNAs (shRNAs). Murine endothelial cells were transduced with lentiviral vectors expressing shRNAs that are complementary to the gene promoter. Gene expression array experiments were conducted to investigate genome-wide mRNA expression changes caused by up- and downregulating VEGF-A. There were several hundreds of differentially expressed genes according to the applied statistical criteria. We noticed that the effects of downregulating VEGF-A were much more wide-spread than the effects of VEGF-A upregulation. Our in silico analysis revealed that a number of different biological processes are altered due to epigenetic effects on VEGF-A expression. One of the main regulators of VEGF-A mediated transcriptional response was found to be transcription factor ATF-4. This is the first study showing the transcriptional response to epigenetic modification of VEGF-A expression in endothelial cells. Epigenetic gene regulation represents a natural gene regulatory mechanism and these results reveal previously unknown implications of VEGF-A regulation in endothelial cells.
Highlights
Vascular endothelial growth factor (VEGF-A) is a key regulator of angiogenesis in many diseases, such as cancer and cardiovascular diseases [1]
These processes have been studied in plants for a long time, but when Morris et al [6] found that small RNAs directed to the gene promoters induce transcriptional gene silencing (TGS) and a little later Li et al [7] showed that they can induce transcriptional gene activation (TGA), their potential as therapeutics was quickly realized
Vascular endothelial growth factor A (VEGF-A) is a mitogen that acts on endothelial cells and has various effects, including mediation of angiogenesis and vasculogenesis
Summary
Vascular endothelial growth factor (VEGF-A) is a key regulator of angiogenesis in many diseases, such as cancer and cardiovascular diseases [1]. It has become evident that small RNAs, such as miRNA, siRNA or shRNA, can regulate target gene expression via promoter targeted epigenetic modifications [6,7,8]. These processes have been studied in plants for a long time, but when Morris et al [6] found that small RNAs directed to the gene promoters induce transcriptional gene silencing (TGS) and a little later Li et al [7] showed that they can induce transcriptional gene activation (TGA), their potential as therapeutics was quickly realized. The specificity and safety of these promoter targeted small RNAs must be evaluated before clinical trials
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