2. Academic Validation
  3. Herpesviruses mimic zygotic genome activation to promote viral replication

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

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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