DOT1L promotes angiogenesis through cooperative regulation of VEGFR2 with ETS-1

Histone methyltransferase DOT1L is implicated in various biological processes including cell proliferation, differentiation and embryogenesis. Gene ablation of Dot1l results in embryonic lethality and cardiovascular defects including decreased vasculature. However, how DOT1L might contribute to the development of vasculature is not clear. Here, we report that DOT1L is required for angiogenesis. We demonstrated that silencing of DOT1L in human umbilical vein endothelial cells (HUVECs) leads to decreased cell viability, migration, tube formation, and capillary sprout formation in vitro, as well as reduced formation of functional vascular networks in matrigel plugs in vivo. Genome-wide analysis of DOT1L targets via H3K79me2 ChIP-seq annotation in HUVECs identified a number of genes including VEGFR2 that are critically involved in angiogenesis. We showed that DOT1L cooperates with transcription factor ETS-1 to stimulate the expression of VEGFR2, thereby activating ERK1/2 and AKT signaling pathways and promoting angiogenesis. Our study revealed a mechanistic role for DOT1L in the promotion of angiogenesis, adding to the understanding of the biological function of this histone methyltransferase.