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2018 ; 293
(28
): 11109-11118
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The transcription factor Vezf1 represses the expression of the antiangiogenic
factor Cited2 in endothelial cells
#MMPMID29794136
AlAbdi L
; He M
; Yang Q
; Norvil AB
; Gowher H
J Biol Chem
2018[Jul]; 293
(28
): 11109-11118
PMID29794136
show ga
Formation of the vasculature by angiogenesis is critical for proper development,
but angiogenesis also contributes to the pathogenesis of various disorders,
including cancer and cardiovascular diseases. Vascular endothelial zinc finger 1
(Vezf1), is a Krüppel-like zinc finger protein that plays a vital role in
vascular development. However, the mechanism by which Vezf1 regulates this
process is not fully understood. Here, we show that Vezf1(-/-) mouse embryonic
stem cells (ESC) have significantly increased expression of a stem cell factor,
Cbp/p300-interacting transactivator 2 (Cited2). Compared with WT ESCs, Vezf1(-/-)
ESCs inefficiently differentiated into endothelial cells (ECs), which exhibited
defects in the tube-formation assay. These defects were due to reduced activation
of EC-specific genes concomitant with lower enrichment of histone 3 acetylation
at Lys(27) (H3K27) at their promoters. We hypothesized that overexpression of
Cited2 in Vezf1(-/-) cells sequesters P300/CBP away from the promoters of
proangiogenic genes and thereby contributes to defective angiogenesis in these
cells. This idea was supported by the observation that shRNA-mediated depletion
of Cited2 significantly reduces the angiogenic defects in the Vezf1(-/-) ECs. In
contrast to previous studies that have focused on the role of Vezf1 as a
transcriptional activator of proangiogenic genes, our findings have revealed a
role for Vezf1 in modulating the expression of the antiangiogenic factor Cited2.
Vezf1 previously has been characterized as an insulator protein, and our results
now provide insights into the mechanism, indicating that Vezf1 can block
inappropriate, nonspecific interactions of promoters with cis-located enhancers,
preventing aberrant promoter activation.