Viral transcriptional regulators extensively rewire host pathways through diverse mechanisms
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 mechanistic links to disease. Together, we provide a comprehensive resource for understanding and targeting viral control of human transcription.
Authors
- Michael S. Calderwood (ORCID: https://orcid.org/0000-0002-3803-0438)
- Burhan Engіn (ORCID: https://orcid.org/0000-0002-5140-1926)
- Shubham Khetan (ORCID: https://orcid.org/0000-0001-8347-7493)
- Zhaorong Li (ORCID: https://orcid.org/0000-0002-5268-6986)
- Martha L. Bulyk (ORCID: https://orcid.org/0000-0002-3456-4555)
- Luis F. Soto (ORCID: https://orcid.org/0000-0002-6348-6437)
- Juan I. Fuxman Bass (ORCID: https://orcid.org/0000-0001-9457-1207)
- Tong Hao (ORCID: https://orcid.org/0000-0001-7908-3256)
- Sakshi Shah (ORCID: https://orcid.org/0000-0002-2075-6900)
- Marc Vidal (ORCID: https://orcid.org/0000-0003-3391-5410)
- James E. Corban (ORCID: https://orcid.org/0000-0002-0132-4352)
- Clarissa Santoso (ORCID: https://orcid.org/0000-0002-2743-7240)
- 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)
- Lucía Martínez Cuesta (ORCID: https://orcid.org/0000-0002-8728-0484)
- Matthew T. Weirauch (ORCID: https://orcid.org/0000-0001-7977-9122)
- Jaice T. Rottenberg (ORCID: https://orcid.org/0000-0002-0225-4608)
- Philipp Trollmann
- Phillip J. Dexheimer (ORCID: https://orcid.org/0000-0003-3965-6894)
- Anna Berenson (ORCID: https://orcid.org/0000-0002-3782-6186)
- Kerstin Spirohn-Fitzgerald
- Xing Liu (ORCID: https://orcid.org/0000-0002-3467-7103)
- Ryan Lane (ORCID: https://orcid.org/0009-0009-0513-9849)
- C Lee
- George Muñoz-Esquivel
- Mohamed Y. ElSadec
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 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)
- Children's Cancer Center (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-02
- DOI
- https://doi.org/10.64898/2025.12.01.691387
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00