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

Nature Medicine volume 15, pages 1312–1317 (2009)Cite this article

Abstract

Reversible methylation of histone tails serves as either a positive signal recognized by transcriptional assemblies or a negative signal that result in repression1,2,3,4. Invading viral pathogens that depend upon the host cell's transcriptional apparatus are also subject to the regulatory impact of chromatin assembly and modifications5,6,7,8. 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 complexes9,10, 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.

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Figure 1: LSD1 is crucial for viral activator–mediated transcription of VZV IE and HSV IE model promoters.
Figure 2: An HCF-1–LSD1 complex is essential for α-herpesvirus IE gene transcription.
Figure 3: Inhibition of LSD1 with MAOIs blocks α-herpesviral lytic gene expression.
Figure 4: Inhibition of LSD1 with MAOIs blocks HSV-1 reactivation from latency.

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Acknowledgements

We thank J. Skinner for expert statistical analysis of the experimental data; B. Moss, J. Yewdell, T. Pierson, J. Bennink and A. McBride for critical discussions and comments on this manuscript; members of the Molecular Genetics Section of the Laboratory of Viral Diseases for discussion, advice and technical assistance; the US National Institute of Allergy and Infectious Diseases Bld33 Animal Care Facility staff; N. Fraser (University of Pennsylvania School of Medicine) for HSV-1 strain 17, W. Ruyechan (University at Buffalo, State University of New York) for ICP8–specific sera and X. Chen (University of California at Davis) for MCF7 inducible LSD shRNA cells. These studies were supported by the Laboratory of Viral Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health.

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  1. Aarthi Narayanan

    Present address: Present address: George Mason University, National Center for Biodefense and Infectious Diseases, Manassas, Virginia, USA.,

Authors and Affiliations

  1. Molecular Genetics Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA

    Yu Liang, Jodi L Vogel, Aarthi Narayanan, Hua Peng & Thomas M Kristie

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Contributions

Y.L. performed ChIP, quantitative PCR, immunofluorescence and animal reactivation studies; A.N. and H.P. performed ChIP and quantitative PCR analyses; J.L.V. performed reporter and immunoprecipitation assays; T.M.K. designed the study, performed animal reactivation studies and wrote the paper. J.L.V. and A.N. contributed equally to this study. All authors discussed the results and commented on the manuscript.

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Correspondence to Thomas M Kristie.

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The US National Institutes of Health Department of Health and Human Services has filed US patent application No. 61/083,304 and international patent application No. PCT/US2009/051557 for methods of preventing infection by herpes viruses or treating reactivation after latency in a host by inhibitors of the Lsd1 protein.

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Liang, Y., Vogel, J., Narayanan, A. et al. Inhibition of the histone demethylase LSD1 blocks α-herpesvirus lytic replication and reactivation from latency. Nat Med 15, 1312–1317 (2009). https://doi.org/10.1038/nm.2051

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