Figure 6.

Model for Hdac3 regulation of LPS-mediated gene expression and function in microglia. Hdac3 represses baseline gene expression through deacetylation of H3K27ac and H3K9ac marked histones. Upon LPS stimulation Hdac3 releases, allowing for increased histone acetylation and immune activation. In the presence of RGFP966, Hdac3’s deacetylase activity is blocked, allowing for increased histone acetylation at baseline and an aberrant increase in baseline gene expression. LPS treatment combined with inhibition of Hdac3 results in hyper-induction of Hdac3 target genes and a lack of suppression of genes normally repressed by LPS. These gene expression shifts ultimately culminate in repressed NO release and increased phagocytosis, driving microglia towards a phenotype that promotes debris clearance. Hdac3 inhibition may drive the changes in NO and phagocytosis through modulation of arginine usage in response to LPS by increasing Arg1 expression and pushing the reaction away from NO generation.