Rnf20 levels modulate the VEGF-Notch signaling circuits during sprouting angiogenesis [ChIP-seq]

Tight control of cell fate choices is crucial for proper vessel development. Here we show that Rnf20, the major E3 ubiquitin ligase of histone H2B, plays a key role in the tight control of VEGF-Notch signaling, which is crucial for proper vessel growth and patterning, as well as for the dynamic tip-stalk cell fate at the vascular front. We demonstrate that Rnf20 is dynamically expressed in the developing retina and controls vessel growth through two distinct modes of action. On the one hand, it restricts gene activation by the endothelial transcription factor ERG and on the other, it orchestrates large-scale mRNA processing events, which change the bioavailability and function of critical pro-angiogenic factors. We show that Rnf20 plays a key role for the upregulation of both VEGFR2 through alternative polyadenylation and VEGFA through intron inclusion, as well as for suppressing the ability of Notch1 to bind to chromatin. Interestingly, perturbations of RNF20 have been associated with complex cardiovascular malformations in human patients, suggesting that delineating the mechanisms that control Rnf20 expression and activity may provide new insights into diseases caused by vascular dysfunction.