Proposed model of regulation of VWF basal and activated transcription by E4BP4. (A) In non–VWF-expressing cells, positive regulatory transcription factors are absent, and E4BP4 is phosphorylated, binds directly to the VWF E4BP4 element, and inhibits basal levels of transcription.³⁴  (B) In VWF-expressing cells, positive regulatory transcription factors are present and productive transcription occurs. E4BP4 is not phosphorylated, or is in some way modified, and cannot directly interact with the VWF E4BP4 binding element. Activated VWF expression is restrained through coordinated binding of E4BP4 first with an unknown factor, presumably a component of the preinitiation complex (PIC), and then by binding with the VWF E4BP4 element. (C) In VWF-expressing cells, E4BP4 cannot directly interact with the VWF E4BP4 binding element. Instead, the E4BP4 repressor domain is able to sequester negative regulators of transcription, such as NC2, and ultimately facilitate promoter activity.^31,43  Relative changes in the quantity and/or types of E4BP4 may regulate the activities of these 2 mechanisms in VWF-expressing cells.