Inhibition of the histone demethylase LSD1 blocks alpha-herpesvirus 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. 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.
Liang
Yu
Y
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, MD, USA.
Vogel
Jodi L
JL
Narayanan
Aarthi
A
Peng
Hua
H
Kristie
Thomas M
TM
D000818:Animals; D002461:Cell Line, Transformed; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D005724:Ganglia / Q000166:cytology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D018259:Herpesvirus 1, Human / Q000502:physiology*; D014645:Herpesvirus 3, Human / Q000502:physiology; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D051863:Host Cell Factor C1 / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010293:Pargyline / Q000494:pharmacology; D010622:Phencyclidine / Q000031:analogs & derivatives; D010880:Piperidines / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D018139:Simplexvirus / Q000502:physiology; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; D008996:Monoamine Oxidase Inhibitors; D010880:Piperidines; D034741:RNA, Small Interfering; D013876:Thiophenes; D049452:Green Fluorescent Proteins; C012058:tenocyclidine; D010293:Pargyline; D056466:Histone Demethylases; C495195:KDM1A protein, human; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D010622:Phencyclidine; D008239:Lysine