Herpesviruses mimic zygotic genome activation to promote viral replication

  • Nat Commun. 2025 Jan 16;16(1):710. doi: 10.1038/s41467-025-55928-5.
Eva Neugebauer  #  1  2  3 ,  Stephanie Walter  #  4 ,  Jiang Tan  #  1 ,  Nir Drayman  5 ,  Vedran Franke  6 ,  Michiel van Gent  7 ,  Sandra Pennisi  1 ,  Pia Veratti  1 ,  Karla S Stein  1 ,  Isabelle Welker  1 ,  Savaş Tay  8 ,  Georges M G M Verjans  7 ,  H T Marc Timmers  9 ,  Altuna Akalin  6 ,  Markus Landthaler  6 ,  Armin Ensser  4 ,  Emanuel Wyler  6 ,  Florian Full  10  11
Affiliations
  • 1. Institute of Virology, University Medical Center, and Faculty of Medicine, Albert-Ludwig-University Freiburg, Freiburg, Germany.
  • 2. Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany.
  • 3. Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • 4. Institute for Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
  • 5. The Department of Molecular Biology and Biochemistry, the Center for Virus Research and the Center for Complex Biological Systems, The University of California, Irvine, Irvine, CA, 92697, USA.
  • 6. Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Helmholtz Society, Berlin, Germany.
  • 7. HerpesLabNL, Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands.
  • 8. The Pritzker School for Molecular Engineering, The University of Chicago, Chicago, IL, 60637, USA.
  • 9. German Cancer Consortium (DKTK), partner site Freiburg, a partnership between the DKFZ and Medical Center-University of Freiburg, and Department of Urology, Medical Center-University of Freiburg, Freiburg, Germany.
  • 10. Institute of Virology, University Medical Center, and Faculty of Medicine, Albert-Ludwig-University Freiburg, Freiburg, Germany. [email protected].
  • 11. German Consulting Laboratory for HSV and VZV, Medical Center - University of Freiburg, Freiburg, Germany. [email protected].
  • # Contributed equally.
PMID: 39814710 DOI: 10.1038/s41467-025-55928-5
Abstract

Zygotic genome activation (ZGA) is crucial for maternal to zygotic transition at the 2-8-cell stage in order to overcome silencing of genes and enable transcription from the zygotic genome. In humans, ZGA is induced by DUX4, a pioneer factor that drives expression of downstream germline-specific genes and retroelements. Here we show that herpesviruses from all subfamilies, papillomaviruses and Merkel cell polyomavirus actively induce DUX4 expression to promote viral transcription and replication. Analysis of single-cell Sequencing data sets from patients shows that viral DUX4 activation is of relevance in vivo. Herpes-simplex virus 1 (HSV-1) immediate early proteins directly induce expression of DUX4 and its target genes, which mimics zygotic genome activation. Upon HSV-1 Infection, DUX4 directly binds to the viral genome and promotes viral transcription. DUX4 is functionally required for Infection, since genetic depletion by CRISPR/Cas9 as well as degradation of DUX4 by nanobody constructs abrogates HSV-1 replication. Our results show that DNA viruses including herpesviruses mimic an embryonic-like transcriptional program that prevents epigenetic silencing of the viral genome and facilitates herpesviral gene expression.

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