Etv6-dependent positive and negative gene regulatory network controls vegfa expression in vivo [RNA-seq]

VEGFA signaling is crucial for physiological and pathological angiogenesis and hematopoiesis. Although many context-dependent signaling pathways downstream of VegfA have been uncovered, vegfa transcriptional regulation in vivo is unclear. Here, we show that ETS transcription factor Etv6 positively regulates vegfa expression during blood stem cell development through multiple transcriptional inputs. In agreement with its established repressive functions, Etv6 directly inhibits expression of vegfa repressor foxo3. Surprisingly, it also directly activates expression of vegfa activator klf4. Finally, it indirectly binds to vegfa promoter by the recruiment of Klf4. Thus, our work uncovers a dual function for Etv6, as both a transcriptional repressor and activator, in controlling a major signaling pathway.

血管内皮生长因子A（VEGFA）信号通路对于生理及病理性血管生成与造血过程均至关重要。尽管目前已揭示了诸多情境依赖性的VEGFA下游信号通路，但体内VEGFA的转录调控机制仍不明晰。本研究发现，ETS家族转录因子（ETS transcription factor）Etv6可通过多重转录调控输入，在造血干细胞发育过程中正向调控vegfa的表达。与其已被证实的抑制性功能相符，Etv6可直接抑制VEGFA的阻遏因子foxo3的表达。令人意外的是，其同时可直接激活VEGFA的激活因子klf4的表达。最终，其通过招募Klf4间接结合至vegfa启动子（promoter）区域。综上，本研究揭示了Etv6兼具转录阻遏与激活双重功能，可调控这一核心信号通路。