Reversible methylation of histone tails serves as either a positive signal 
recognized by transcriptional assemblies or a negative signal that result in 
repression. Invading viral pathogens that depend upon the host cell's 
transcriptional apparatus are also subject to the regulatory impact of chromatin 
assembly and modifications. Here we show that infection by the 
alpha-herpesviruses, herpes simplex virus (HSV) and varicella zoster virus 
(VZV), results in the rapid accumulation of chromatin bearing repressive histone 
H3 Lys9 methylation. To enable expression of viral immediate early (IE) genes, 
both viruses use the cellular transcriptional coactivator host cell factor-1 
(HCF-1) to recruit the lysine-specific demethylase-1 (LSD1) to the viral 
immediate early promoters. Depletion of LSD1 or inhibition of its activity with 
monoamine oxidase inhibitors (MAOIs) results in the accumulation of repressive 
chromatin and a block to viral gene expression. As HCF-1 is a component of the 
Set1 and MLL1 histone H3 Lys4 methyltransferase complexes, it thus coordinates 
modulation of repressive H3 Lys9 methylation levels with addition of activating 
H3 Lys4 trimethylation marks. Strikingly, MAOIs also block the reactivation of 
HSV from latency in sensory neurons, indicating that the HCF-1 complex is a 
crucial component of the reactivation mechanism. The results support 
pharmaceutical control of histone modifying enzymes as a strategy for 
controlling herpesvirus infections.