Functional characterization of viral transcriptional regulators reveals extensive rewiring of host pathways
Viral transcriptional regulators (vTRs) reprogram host gene regulatory networks to promote replication, persistence, and immune evasion. Despite the identification of hundreds of vTRs in human viruses, how they rewire host pathways remains unclear. Here, we systematically profiled 95 vTRs from diverse human viruses across multiple functional assays. vTRs perturb immune, cell proliferation/death, and signaling pathways through various mechanisms; some bind DNA directly, others cooperate or antagonize human transcription factors (hTFs), and some remodel chromatin. vTRs can act as activators or repressors and recruit similar but not identical repertoires of proteins as hTFs. These findings reveal vTRs as versatile transcriptional modulators that converge on conserved host “pressure points” while diversifying across pathways to promote viral replication and persistence. Notably, many vTR dysregulate genes within autoimmune, neurological, and cardiovascular risk loci, revealing potential mechanistic links to disease. Together, we provide a large-scale resource for understanding and targeting viral control of human transcription. The authors here show how viral transcriptional regulators reprogram human gene activity through diverse mechanisms, revealing shared strategies used by different viruses to control host pathways and potentially influence disease risk.
Authors
- Shubham Khetan (ORCID: https://orcid.org/0000-0001-8347-7493)
- Berkay ENGİN (ORCID: https://orcid.org/0000-0002-0398-6843)
- Zhaorong Li (ORCID: https://orcid.org/0000-0002-5268-6986)
- Martha L. Bulyk (ORCID: https://orcid.org/0000-0002-3456-4555)
- Leah C. Kottyan (ORCID: https://orcid.org/0000-0003-3979-2220)
- Juan I. Fuxman Bass (ORCID: https://orcid.org/0000-0001-9457-1207)
- Tong Hao (ORCID: https://orcid.org/0000-0001-7908-3256)
- Michael A. Calderwood (ORCID: https://orcid.org/0000-0001-6475-1418)
- Sakshi Shah (ORCID: https://orcid.org/0000-0002-2075-6900)
- Marc Vidal (ORCID: https://orcid.org/0000-0003-3391-5410)
- Kerstin Spirohn (ORCID: https://orcid.org/0000-0002-2071-1606)
- James E. Corban (ORCID: https://orcid.org/0000-0002-0132-4352)
- Nidhi Sahni (ORCID: https://orcid.org/0000-0002-9155-5882)
- S. Stephen Yi (ORCID: https://orcid.org/0000-0003-0047-8103)
- Yunwei Lu (ORCID: https://orcid.org/0009-0006-0043-4521)
- Srivatsan Raman (ORCID: https://orcid.org/0000-0003-2461-1589)
- Matthew T. Weirauch (ORCID: https://orcid.org/0000-0001-7977-9122)
- Philipp Trollmann
- Phillip J. Dexheimer (ORCID: https://orcid.org/0000-0003-3965-6894)
- Anna Berenson (ORCID: https://orcid.org/0000-0002-3782-6186)
- Xing Liu (ORCID: https://orcid.org/0000-0002-7480-5085)
- Ryan Lane (ORCID: https://orcid.org/0009-0009-0513-9849)
- C Lee
- Matthew Hass
- George D. Muñoz-Esquivel (ORCID: https://orcid.org/0009-0007-3765-9967)
- Lucia Martinez-Cuesta
- Jaice T. Rottenberg
- Mohamed Y. ElSadec
- Clarissa Santoso
- Cailing Yin
- Luis F. Soto-Ugaldi
Institutions
- Boston University (US)
- Brigham and Women's Hospital (US)
- Cincinnati Children's Hospital Medical Center (US)
- University of Wisconsin–Madison (US)
- Harvard University (US)
- Baylor University (US)
- Baylor College of Medicine (US)
- National University of San Marcos (PE)
- Great Lakes Bioenergy Research Center (US)
- Tri-Institutional PhD Program in Chemical Biology (US)
- Centro Científico Tecnológico - Tandil (AR)
- Boston VA Research Institute (US)
- Dana-Farber Cancer Institute (US)
- Houston Institute for Clinical Research (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-17
- DOI
- https://doi.org/10.1038/s41467-026-77780-x
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Alfred P. Sloan Foundation
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Division of Cancer Prevention, National Cancer Institute
- National Institutes of Health
- National Human Genome Research Institute
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke
- National Institute of Arthritis and Musculoskeletal and Skin Diseases