Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) causes primary effusion lymphoma (PEL). The cellular transcription factor (TF) interferon (IFN) regulatory factor 4 (IRF4) is an essential oncogene in PEL, but its specific role in PEL and how KSHV deregulates IRF4 remain unknown. Here, we report that the KSHV latency protein viral interferon regulatory factor 3 (vIRF3) cooperates with IRF4 and cellular BATF (basic leucine zipper ATF-like TF) to drive a super-enhancer (SE)-mediated on-cogenic transcriptional program in PEL. Chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-Seq) experiments demonstrated that IRF4, vIRF3, and BATF cooccupy the SEs of key survival genes, in a pattern that is distinct from those seen with other IRF4-driven malignancies. All three proteins coopera-tively drive SE-mediated IRF4 overexpression. Inactivation of vIRF3 and, to a lesser extent, BATF phenocopies the gene expression changes and loss of cellular viability observed upon inactivation of IRF4. In sum, this work suggests that KSHV vIRF3 and cellular IRF4 and BATF cooperate as oncogenic transcription factors on SEs to promote cellular survival and proliferation in KSHV-associated lymphomas. IMPORTANCE Kaposi’s sarcoma-associated herpesvirus (KSHV) causes the aggressive disease primary effusion lymphoma (PEL). Here, we show that a viral transcription factor (vIRF3) cooperates with the cellular transcription factor IRF4 to control an on-cogenic gene expression program in PEL cells. These proteins promote KSHV-mediated B cell transformation by activating the expression of prosurvival genes through super-enhancers. Our report thus demonstrates that this DNA tumor virus encodes a transcription factor that functions with cellular IRF4 to drive oncogenic transcriptional reprogramming.
| Original language | English (US) |
|---|---|
| Article number | e01457-20 |
| Pages (from-to) | 1-23 |
| Number of pages | 23 |
| Journal | mBio |
| Volume | 11 |
| Issue number | 4 |
| DOIs | |
| State | Published - Jul 1 2020 |
Funding
This study was supported by National Institutes of Health/National Cancer Institute Grants R21 CA210904 and R01CA247619, by Searle and Zell Scholar Awards from the Robert H. Lurie Comprehensive Cancer Center (E.G.), by a Chicago Biomedical Consortium Postdoctoral Award PDR-061 (M.M.), by R01 AI140855 (J.N.), and by Landesforsc-hungsfoerderung Hamburg grant LFF-FV-044 (A.G.). The content is solely our responsibility and does not necessarily represent the official views of the funding agencies. We thank the NU Flow Cytometry Core Facility for assistance with cell sorting (supported by NCI Grant CA060553 to the RHLCC), Matthew Schipma at the NUSeq Core Facility for differential gene expression analysis of mRNA-Seq data, Bo Zhao for discussions of unpublished data and EBNA3C data, and members of the Gottwein lab for feedback on the manuscript. This study was supported by National Institutes of Health/National Cancer Institute Grants R21 CA210904 and R01CA247619, by Searle and Zell Scholar Awards from the Robert H. Lurie Comprehensive Cancer Center (E.G.), by a Chicago Biomedical Consor-tium Postdoctoral Award PDR-061 (M.M.), by R01 AI140855 (J.N.), and by Landesforsc-hungsfoerderung Hamburg grant LFF-FV-044 (A.G.). The content is solely our respon-sibility and does not necessarily represent the official views of the funding agencies.
Keywords
- EBNA3C
- EBV
- HBZ
- HTLV-1
- IRF4
- KSHV
- LANA2
- Master transcription factor
- Primary effusion lymphoma
- Super-enhancer
- Transcriptional reprogramming
- VIRF3
ASJC Scopus subject areas
- Virology
- Microbiology
