KSHV-encoded vIRF3 cooperates with cellular IRF4 to drive super-enhancer activity through complex DNA elements.
- 1Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, United States.
- 2Departments of Biochemistry and Molecular Genetics and Preventive Medicine (Biostatistics and Informatics), Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, United States.
Abstract
The Kaposi's sarcoma-associated herpesvirus oncoprotein vIRF3 is essential for primary effusion lymphoma (PEL) cell survival and cooperates with cellular interferon regulatory factor 4 (IRF4) to activate super-enhancers (SEs) controlling MYC and IRF4. However, the DNA sequence requirements for this cooperation are unknown. Using reporter assays, we mapped vIRF3/IRF4 responsiveness within the IRF4-SE to an ∼83-bp element activated by vIRF3 alone and cooperatively by vIRF3 and IRF4. vIRF3-dependent activation required an AP-1 motif, whereas cooperation with IRF4 required IRF4 DNA binding and IRF-related motifs outside canonical AP-1-IRF composite elements (AICEs). These motifs were necessary but insufficient outside their native sequence context, indicating a requirement for extended flanking sequences. DNA pulldowns revealed distinct motif requirements for vIRF3 and IRF4 association with the IRF4-SE. A distal MYC-SE required a similarly extended region containing a functional AICE2 motif, with vIRF3 activity depending primarily on its AP-1 half-site. Motif requirements were preserved in integrated reporter assays. BATF promoted vIRF3/IRF4-dependent activation preferentially in integrated reporters and was required to maintain vIRF3 and IRF4 occupancy at the endogenous MYC-SE. These findings define context-dependent DNA and cofactor requirements through which vIRF3 co-opts IRF4-regulated oncogenic enhancers in PEL.
Related
- A transcriptional cofactor GRIP1 drives PPARγ DNA binding and p300-dependent enhancer activity during homeostatic macrophage polarization
- Acute degron-mediated RUNX1 loss reprograms enhancer activity associated with epithelial destabilization and initiation of cancer hallmarks
- Enhancer control of promoter activity and variability via frequency modulation of clustered transcriptional bursts
- The NuRD complex shapes RNA polymerase III activity at highly expressed tRNA gene clusters, tuning the dynamic range of cellular tRNA pools
- Isoenzyme-specific determination of glutathione peroxidase activity in cell lysates and GPX1/GPX4-HiBiT cellular target engagement
BibTeX
@article{liang2026kshvencoded,
title = {{KSHV-encoded vIRF3 cooperates with cellular IRF4 to drive super-enhancer activity through complex DNA elements.}},
author = {Ziyan Liang and Christine B Magdongon and Haocong Katherine Ma and Maureen E Haynes and Jingyi Lu and Elizabeth T Bartom and Eva Gottwein},
journal = {Nucleic acids research},
year = {2026},
month = sep,
doi = {10.1093/nar/gkag942},
url = {https://europepmc.org/article/MED/42831422},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - KSHV-encoded vIRF3 cooperates with cellular IRF4 to drive super-enhancer activity through complex DNA elements.
AU - Ziyan Liang
AU - Christine B Magdongon
AU - Haocong Katherine Ma
AU - Maureen E Haynes
AU - Jingyi Lu
AU - Elizabeth T Bartom
AU - Eva Gottwein
PY - 2026
DA - 2026/09/01
JO - Nucleic acids research
DO - 10.1093/nar/gkag942
UR - https://europepmc.org/article/MED/42831422
AB - The Kaposi's sarcoma-associated herpesvirus oncoprotein vIRF3 is essential for primary effusion lymphoma (PEL) cell survival and cooperates with cellular interferon regulatory factor 4 (IRF4) to activate super-enhancers (SEs) controlling MYC and IRF4. However, the DNA sequence requirements for this cooperation are unknown. Using reporter assays, we mapped vIRF3/IRF4 responsiveness within the IRF4-SE to an ∼83-bp element activated by vIRF3 alone and cooperatively by vIRF3 and IRF4. vIRF3-dependent activation required an AP-1 motif, whereas cooperation with IRF4 required IRF4 DNA binding and IRF-related motifs outside canonical AP-1-IRF composite elements (AICEs). These motifs were necessary but insufficient outside their native sequence context, indicating a requirement for extended flanking sequences. DNA pulldowns revealed distinct motif requirements for vIRF3 and IRF4 association with the IRF4-SE. A distal MYC-SE required a similarly extended region containing a functional AICE2 motif, with vIRF3 activity depending primarily on its AP-1 half-site. Motif requirements were preserved in integrated reporter assays. BATF promoted vIRF3/IRF4-dependent activation preferentially in integrated reporters and was required to maintain vIRF3 and IRF4 occupancy at the endogenous MYC-SE. These findings define context-dependent DNA and cofactor requirements through which vIRF3 co-opts IRF4-regulated oncogenic enhancers in PEL.
SN - 0305-1048
SN - 1362-4962
ER -