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

• Published in: Nature medicine Vol. 15; no. 11; pp. 1312 - 1317
• Main Authors: Liang, Yu, Vogel, Jodi L, Narayanan, Aarthi, Peng, Hua, Kristie, Thomas M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2009; Nature Publishing Group
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Transformed; Chromatin Immunoprecipitation - methods; DNA Replication - drug effects; DNA Replication - physiology; Enzyme Activation - drug effects; Ganglia - cytology; Gene Expression Regulation, Viral - drug effects; Gene Expression Regulation, Viral - physiology; Genetic aspects; Green Fluorescent Proteins - genetics; Herpesvirus 1, Human - physiology; Herpesvirus 3, Human - physiology; Herpesviruses; Histone Demethylases - antagonists & inhibitors; Histone Demethylases - genetics; Histone Demethylases - metabolism; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Histones; Host Cell Factor C1 - metabolism; Humans; Infectious Diseases; letter; Lysine - metabolism; Metabolic Diseases; Methylation; Mice; Molecular Medicine; Monoamine Oxidase Inhibitors - pharmacology; Mutation - genetics; Neurons - drug effects; Neurons - metabolism; Neurosciences; Pargyline - pharmacology; Phencyclidine - analogs & derivatives; Physiological aspects; Piperidines - pharmacology; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - physiology; Reaction Time - drug effects; RNA, Small Interfering - metabolism; RNA, Small Interfering - pharmacology; Simplexvirus - physiology; Thiophenes - pharmacology; Time Factors; Transfection - methods; Viral genetics; Virus Replication - drug effects; Virus Replication - physiology; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2051

Viral gene expression can be regulated by chromatin methylation and demethylation. Thomas Kristie and his colleagues have identified a histone demethylase that is required to remove repressive methylation from the immediate early promoters of two α-herpesviruses. Monoamine oxidase inhibitors, which block this demethylase, prevented lytic replication and reactivation from latency. Reversible methylation of histone tails serves as either a positive signal recognized by transcriptional assemblies or a negative signal that result in repression 1 , 2 , 3 , 4 . Invading viral pathogens that depend upon the host cell's transcriptional apparatus are also subject to the regulatory impact of chromatin assembly and modifications 5 , 6 , 7 , 8 . Here we show that infection by the α-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 9 , 10 , 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.