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Epigenetic transcriptional repression of cellular genes by a viral SET protein

Nature Cell Biology volume 10, pages 1114–1122 (2008)Cite this article

Abstract

Viruses recruit host proteins to secure viral genome maintenance and replication. However, whether they modify host histones directly to interfere with chromatin-based transcription is unknown. Here we report that Paramecium bursaria chlorella virus 1 (PBCV-1) encodes a functional SET domain histone Lys methyltransferase (HKMTase) termed vSET, which is linked to rapid inhibition of host transcription after viral infection. We show that vSET is packaged in the PBCV-1 virion, and that it contains a nuclear localization signal and probably represses host transcription by methylating histone H3 at Lys 27 (H3K27), a modification known to trigger gene silencing in eukaryotes. We also show that vSET induces cell accumulation at the G2/M phase by recruiting the Polycomb repressive complex CBX8 to the methylated H3K27 site in a heterologous system. vSET-like proteins that have H3K27 methylation activity are conserved in chlorella viruses. Our findings suggest a viral mechanism to repress gene transcription by direct modification of chromatin by PBCV-1 vSET.

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Figure 1: Presence of vSET in PBCV-1 virions.
Figure 2: Methylation of Chlorella NC64A histone H3K27 by vSET.
Figure 3: Nuclear localization and H3K27 methylation activity of vSET.
Figure 4: Repression of gene transcription by vSET H3K27 methylation activity.
Figure 5: HKMT activity of SET proteins from chlorella viruses.

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Acknowledgements

We thank L.W. Enquist for the Us9–GFP construct, M. Ptashne for the Gal4-DBD construct, P. Traber for the firefly luciferase construct, R. Slany for the HOX7A luciferase construct, I. V. Agarkova for the results used in Fig. 1a, and M. Walsh for helpful discussions. Fluorescence microscopy imaging was performed at the Mount Sinai Microscopy Shared Resource Facility supported in part with funding from NIH-NCI shared resources grant. This work was supported by grants from the National Institutes of Health (M.-M.Z. and J.L.V.E.).

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Authors and Affiliations

  1. Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York University, 1425 Madison Avenue, Box 1677, New York, 10029, NY, USA

    Shiraz Mujtaba, Karishma L. Manzur & Ming-Ming Zhou

  2. Department of Plant Pathology and Nebraska Center for Virology, University of Nebraska, Lincoln, 68583, Nebraska, USA

    James R. Gurnon, Ming Kang & James L. Van Etten

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  1. Shiraz Mujtaba
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  5. James L. Van Etten
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  6. Ming-Ming Zhou
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Contributions

S.M. characterized vSET function in mammalian cells; K.L.M. performed the in vitro histone Lys methylation study of vSET and vSET-like proteins; J.R.G. and M.K. conducted the study of PBCV-1 infection of Chlorella cells and vset gene probing of chlorella viruses; M.-M.Z. and J.L.V.E. directed the project and all authors contributed to the preparation of the manuscript.

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Correspondence to James L. Van Etten or Ming-Ming Zhou.

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The authors declare no competing financial interests.

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Supplementary Information

Supplementary Figures S1, S2, S3, S4, S5, Supplementary Tables S1, S2, S3, S4 and Supplementary Methods (PDF 6251 kb)

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Mujtaba, S., Manzur, K., Gurnon, J. et al. Epigenetic transcriptional repression of cellular genes by a viral SET protein. Nat Cell Biol 10, 1114–1122 (2008). https://doi.org/10.1038/ncb1772

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