Abstract 17031: Epigenetic Modifications at VEGFR1 Locus in Response to Angiogenic Signal
Vascular endothelial growth factor (VEGF) and its receptors (VEGFR1/VEGFR2) are primary regulators of angiogenesis. Among them, VEGFR1 has a dual role of either stimulating or suppressing angiogenesis. So, it is highly important to understand the molecular mechanism underlying its regulation. Earlier we found that angiogenic signal-ETS1-HIF2α regulatory axis is involved in the activation of Vegfr1 chromatin domain in endothelial cells. However, the dynamic nucleoprotein structure that assembles at the Vegfr1 chromatin locus is poorly understood. Here, we report that dynamic alteration in Vegfr1 transcription is associated with epigenetic marks that facilitate or repress transcriptional activation. The rapid induction of Vegfr1 transcription in response to angiogenic signal FGF2/EGF in yolk sac endothelial cells (YSECs) is associated with rapid increase in acetylated histone H3 at lysine 9 (H3acK9), 56 (H3acK56) and 27 (H3acK27), levels at the Vegfr1 chromatin domain. A time course analysis revealed that these acetylation levels are gradually reduced with time and is correlated with transcriptional repression of Vegfr1. The increase in acetylation is associated with the induction in expression of histone acetyl transferase, Creb Binding Protein (CBP) in YSECs. Knockdown of CBP by RNA interference inhibited FGF2/EGF induced VEGFR1 expression with loss in histone acetylation marks. Level of repressive modification of histone H3 methylated at lysine27 (H3me3K27) at the Vegfr1 locus correlated with transcriptional repression of Vegfr1. Member of the polycomb group family might regulate the transcriptional repression of Vegfr1 in endothelial cells as well as during differentiation of embryonic stem cells towards endothelial progenitors. This approach will provide important insights about molecular mechanisms of gene regulation in angiogenic signal-activated vs. repressed endothelial cells and will lead to therapeutic modalities for controlling angiogenesis.
- © 2011 by American Heart Association, Inc.