Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells

Abstract

The regulation of acetylation is central for the epigenetic control of lineage-specific gene expression and determines cell fate decisions. We provide evidence that the inhibition of histone deacetylases (HDACs) blocks the endothelial differentiation of adult progenitor cells. To define the mechanisms by which HDAC inhibition prevents endothelial differentiation, we determined the expression of homeobox transcription factors and demonstrated that HoxA9 expression is down-regulated by HDAC inhibitors. The causal involvement of HoxA9 in the endothelial differentiation of adult progenitor cells is supported by the finding that HoxA9 overexpression partially rescued the endothelial differentiation blockade induced by HDAC inhibitors. Knockdown and overexpression studies revealed that HoxA9 acts as a master switch to regulate the expression of prototypical endothelial-committed genes such as endothelial nitric oxide synthase, VEGF-R2, and VE-cadherin, and mediates the shear stress–induced maturation of endothelial cells. Consistently, HoxA9-deficient mice exhibited lower numbers of endothelial progenitor cells and showed an impaired postnatal neovascularization capacity after the induction of ischemia. Thus, HoxA9 is regulated by HDACs and is critical for postnatal neovascularization.

Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells

“…Therefore, our findings that treatment with EZH2 siRNA, which depletes the levels of PRC2 components and trimethylation of H3K27, increases the levels of HOXA9 is consistent with these reports. In addition, our additional findings that treatment with HA-HDIs depletes HOXA9 levels are also consistent with the previous report that HDAC activity is essential for the expression of HOXA9 and for the endothelial commitment of progenitor cells (46). We further show that treatment with HA-HDIs alone or cotreatment with EZH2 siRNA depleted HOXA9 and MEIS1 levels but induced p21 in the AML cells.…”

In vitro differentiation of hepatic progenitor cells from mouse embryonic stem cells induced by sodium butyrate

“…In addition, the majority of the treated cells remained in cell cycle for 3 days after the addition of sodium butyrate, but the cycling fraction decreased to 17% 7 days later [Rambhatla et al, 2003]. It was now established that treatment of cells both in vitro and in vivo with sodium butyrate, a potential histone deacetylase (HDAC) inhibitor, could result in specific functional outcomes such as proliferation, cell cycle arrest, apoptosis, or differentiation [Janson et al, 1997;Sambucetti et al, 1999;Wang et al, 1999;Travers et al, 2002;Camphausen et al, 2004;Hsieh et al, 2004;Bug et al, 2005;Cho et al, 2005;Jiang et al, 2005;Rossig et al, 2005]. Therefore it was assumed that the treatment with sodium butyrate would lead to the cell cycle arrest of the ES cells, and the removal of sodium butyrate might be important for the treated cells to reenter into cell cycle and consequently the cells with the capacity to proliferate and express hepatic linage markers could be acquired.…”

SIRT1 controls endothelial angiogenic functions during vascular growth

“…While the class I and II HDACs are sensitive to trichostatin A (TSA), class III HDACs (SIRTs) are not, and their deacetylase activity uniquely relies on the cofactor nicotinamide adenine dinucleotide (NAD + ). Class I and II HDACs play important roles in the transcriptional control of endothelial gene expression and vascular development (Kim et al 2001;Deroanne et al 2002;Rossig et al 2002Rossig et al , 2005Illi et al 2003Illi et al , 2005Chang et al 2006). Pharmacological inhibition of class I and II HDACs has been shown to block pathological angiogenesis during tumor growth (Kim et al 2001) and to prevent adult progenitor cell differentiation toward the endothelial lineage (Rossig et al 2005).…”