The NFY Transcription Factor Inhibits von Willebrand Factor Promoter Activation in Non-endothelial Cells through Recruitment of Histone Deacetylases

Abstract

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.

Molecular Mechanisms for Transcriptional Regulation of Human High-Affinity IgE Receptor β-Chain Gene Induced by GM-CSF

“…Among the three subunits constituting NFY, A and B-subunits have been reported to bind HDAC and p300/CBP, respectively (24,35). These reports indicate that NFY can directly interact with both histone acetyl transferase and HDAC, which are known to act as a transcriptional coactivator and corepressor, respectively.…”

“…NFY consists of A, B, and C subunits (23), of which the A subunit has been reported to bind HDACs (24). Therefore, we analyzed the interaction between HDACs and the intronic region of the ␤-chain gene by ChIP assays using anti-HDAC1 and anti-HDAC2 Abs (Fig.…”

The histone deacetylase inhibitor trichostatin A induces GADD45γ expression via Oct and NF-Y binding sites

“…Role of co-repressors and co-activators in the regulation of the murine GADD45g promoter NF-Y and Oct-1 can interact with HAT-containing coactivator complexes and HDAC-containing co-repressor complexes (Nagy et al, 1997;Mantovani, 1999;Kakizawa et al, 2001;Park et al, 2002;Peng and Jahroudi, 2003;Huang et al, 2005). We therefore assessed the contribution of these factors to GADD45g promoter activity regulation.…”

“…Because SMRT co-repressor activity can be exerted through its presence in a macromolecular complex containing the HDAC1 (Nagy et al, 1997) and NF-Y inhibits von Willebrand factor promoter activity through recruitment of HDACs (Peng and Jahroudi, 2003), we investigated the involvement of HDAC1 in the regulation of the GADD45g promoter. To this end, an HDAC1 expression plasmid was co-transfected with the À818 to þ 15 promoter reporter plasmid.…”

“…Since Oct-1 and NF-Y can interact with HATcontaining co-activator complexes and HDAC-containing co-repressor complexes (Nagy et al, 1997;Mantovani, 1999;Kakizawa et al, 2001;Park et al, 2002;Peng and Jahroudi, 2003;Huang et al, 2005), we studied the possible role of SMRT, HDAC1, and PCAF in the regulation of the murine GADD45g promoter. SMRT or HDAC1, but not HDAC3, ectopic expression reduced GADD45g promoter activity, while forced expression of PCAF increased it.…”