Abstract

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.

Highlights

  • The circulatory system consists of a highly organized network of blood vessels which deliver nutrients, gases, and hormones throughout the body

  • 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

  • To investigate whether or not DOT1L regulates angiogenesis by controlling the behavior of endothelial cells, we examined the effect of loss-offunction of DOT1L in HUVECs on the cell viability, migration, tube formation, and capillary sprout formation

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Summary

Introduction

The circulatory system consists of a highly organized network of blood vessels which deliver nutrients, gases, and hormones throughout the body. During embryogenesis, proliferating endothelial precursor cells migrate and differentiate to form a primitive lumenized vascular plexus, a process known as vasculogenesis. The vascular plexus significantly sprouts due to capillary branching and is transformed into the highly organized vascular net [1]. In addition to modulating various physiological processes, such as embryonic development and injury response, angiogenesis is involved in pathophysiological conditions, including diabetic retinopathy and tumor growth [2]. Aberrant activation of angiogenesis contributes to tumor development; without blood supply the volume of a tumor nodule cannot exceed 2–3 mm due to hypoxia that results in the death of tumor cells [3]. Strategies targeting angiogenesis have proven to be valuable therapeutic approaches in preventing tumor progression [4], an insightful understanding of the molecular mechanisms of angiogenesis has important implications

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