Herpesviruses mimic zygotic genome activation to promote viral replication

Neugebauer E, Walter S, Tan J, Drayman N, Franke V, van Gent M, Pennisi S, Veratti P, Stein KS, Welker I, Tay S, Verjans GM, Timmers HT, Akalin A, Landthaler M, Enßer A, Wyler E, Full F (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 16

Pages Range: 710-

Journal Issue: 1

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.

Authors with CRIS profile

Stephanie Walter Institute of Clinical and Molecular Virology Armin Enßer Institute of Clinical and Molecular Virology

Involved external institutions

Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch DE Germany (DE) Erasmus University Medical Center (MC) NL Netherlands (NL) Universitätsklinikum Freiburg DE Germany (DE) University of California Los Angeles (UCLA) US United States (USA) (US) University of Chicago US United States (USA) (US)

How to cite

APA:

Neugebauer, E., Walter, S., Tan, J., Drayman, N., Franke, V., van Gent, M.,... Full, F. (2025). Herpesviruses mimic zygotic genome activation to promote viral replication. Nature Communications, 16(1), 710-. https://doi.org/10.1038/s41467-025-55928-5

MLA:

Neugebauer, Eva, et al. "Herpesviruses mimic zygotic genome activation to promote viral replication." Nature Communications 16.1 (2025): 710-.

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