The NFY transcription factor inhibits von Willebrand factor promoter activation in non-endothelial cells through recruitment of histone deacetylases.
Human von Willebrand factor (VWF) gene sequences +155 to +247 contain cis-acting elements that contribute toward endothelial specific activation of the VWF promoter. Analyses of this region demonstrated the presence of a GATA-binding site that is necessary for the promoter activation in endothelial cells. We have reported recently the presence of a novel NFY-binding sequence in this region that does not conform to the consensus NFY-binding sequence CCAAT. NFY was shown to function as a repressor of the VWF promoter through interaction with this novel binding site. Here we report that the NFY interacts with histone deacetylases (HDACs) in a cell type-specific manner and recruits them to the VWF promoter to inhibit the promoter activity in non-endothelial cells. Analyses of the acetylation status of histones in the chromatin region containing the VWF promoter sequences demonstrated that these sequences are associated with acetylated histone H4 specifically in endothelial cells. It was also demonstrated that HDACs are specifically recruited to the same chromatin region in non-endothelial cells. We also demonstrated that GATA6 is the GATA family member that interacts with the VWF promoter and that GATA6 is associated with NFY specifically in non-endothelial cells. We propose that NFY recruits HDACs to the VWF promoter, which may result in deacetylation of GATA6 as well as of histones in non-endothelial cells, thus leading to promoter inactivation. In endothelial cells, however, association of HDACs, NFY, and GATA6 is interrupted potentially through endothelial cell-specific signaling/mechanism, thus favoring the balance toward acetylation and activation of the VWF promoter.
Peng
Yiwen
Y
Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Jahroudi
Nadia
N
D000107:Acetylation; D001483:Base Sequence; D023081:CCAAT-Binding Factor / Q000502:physiology*; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D050993:GATA6 Transcription Factor; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014841:von Willebrand Factor / Q000235:genetics*
D023081:CCAAT-Binding Factor; D017931:DNA Primers; D004268:DNA-Binding Proteins; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D006657:Histones; D014157:Transcription Factors; C402244:nuclear factor Y; D014841:von Willebrand Factor; D006655:Histone Deacetylases