Herpesviruses mimic zygotic genome activation to promote viral replication

Eva Neugebauer, Stephanie Walter, Jiang Tan, Nir Drayman, Vedran Franke, Michiel Gent, Sandra Pennisi, Pia Veratti, Karla S. Stein, Isabelle Welker, Savaş Tay, Georges M. G. M. Verjans, H. T. Marc Timmers, Altuna Akalin, Markus Landthaler, Armin Ensser, Emanuel Wyler and Florian Full ()
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Eva Neugebauer: Albert-Ludwig-University Freiburg
Stephanie Walter: Friedrich-Alexander-Universität Erlangen-Nürnberg
Jiang Tan: Albert-Ludwig-University Freiburg
Nir Drayman: the Center for Virus Research and the Center for Complex Biological Systems, The University of California, Irvine
Vedran Franke: Helmholtz Society
Michiel Gent: Erasmus Medical Center
Sandra Pennisi: Albert-Ludwig-University Freiburg
Pia Veratti: Albert-Ludwig-University Freiburg
Karla S. Stein: Albert-Ludwig-University Freiburg
Isabelle Welker: Albert-Ludwig-University Freiburg
Savaş Tay: The University of Chicago
Georges M. G. M. Verjans: Erasmus Medical Center
H. T. Marc Timmers: Medical Center-University of Freiburg
Altuna Akalin: Helmholtz Society
Markus Landthaler: Helmholtz Society
Armin Ensser: Friedrich-Alexander-Universität Erlangen-Nürnberg
Emanuel Wyler: Helmholtz Society
Florian Full: Albert-Ludwig-University Freiburg

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-55928-5

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