Poster Sessions

V -7

Yu Liang

Y. Liang, A. Narayanan, J. Vogel, T. Kristie

Inhibition of the histone demethylase LSD1 represses α- herpesvirus lytic replication and reactivation from latency

Reversible methylation of histone tails serve as either positive signals recognized by transcriptional assemblies or negative signals 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 α-herpesviruses HSV and VZV results in the rapid accumulation of chromatin bearing repressive histone H3-lysine 9 methylation. To enable expression of viral immediate early (IE) genes, both viruses use the cellular transcriptional coactivator HCF-1 to recruit the demethylase LSD1 to the viral immediate early promoters. Depletion of LSD1 or inhibition of its activity with MAO inhibitors results in the inability to remove repressive chromatin and a block to viral gene expression. As HCF-1 is a component of the Set1 and MLL1 histone H3 lysine 4 methyl-transferase complexes 12, 13, it coordinates removal of repressive methylation with addition of activating lysine 4 trimethylation marks. Strikingly, MAO inhibitors also block the reactivation of HSV from latency in sensory neurons, indicating that the HCF-1 chromatin remodeling complex is a critical component of the reactivation mechanism. The results support pharmaceutical control of histone modifying enzymes as a strategy for controlling herpesvirus infections.