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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2408-2417
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
The NFY transcription factor functions as a repressor and
activator of the von Willebrand factor promoter
Yiwen Peng and
Nadia Jahroudi
From the Department of Medicine, Division of
Cardiology, Albert Einstein College of Medicine, Bronx, NY.
Human von Willebrand factor (VWF) gene sequences  487 to +247
function as an endothelial-specific promoter in vitro. Analysis of the
activation mechanism of the VWF promoter has resulted in the
identification of a number of cis-acting elements and trans-acting factors that regulate its activity. The GATA and Ets transcription factors were shown to function as activators of transcription, whereas
NF1 and Oct1 were shown to repress transcription. We have reported the
presence of another repressor element in exon 1 that interacted with a
protein complex designated "R." In the absence of NF1 binding,
inhibition of this interaction resulted in promoter activation in
nonendothelial cells. We have now identified the "R" protein
complex as the NFY transcription factor. Using DNA methylation
interference assay and base substitution mutation analysis, we show
that NFY interacts with a novel DNA sequence corresponding to
nucleotides +226 to +234 in the VWF promoter that does not conform to
the consensus NFY binding sequence CCAAT. The VWF gene does contain a
CCAAT element that is located downstream of the TATA box and we show
that the NFY factor also interacts with this CCAAT element. Using
antibodies specific against the A, B, and C subunits of NFY, we
demonstrate that the NFY complexes interacting with the CCAAT sequence
have a composition similar to that of the repressor binding to the
first exon sequences. The results of mutation analysis and transfection
studies demonstrated that the interaction of NFY with the upstream
CCAAT element is required for VWF promoter activation. Based on these
results, we hypothesize that NFY can function both as a repressor and
activator of transcription and its function may be modulated through
its DNA binding sequences.
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