Kaposi’s Sarcoma-Associated Herpesvirus Drives a Super-Enhancer-Mediated Survival Gene Expression Program in Primary Effusion Lymphoma

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 repo...

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Autores principales:	Mark Manzano, Thomas Günther, Hyunwoo Ju, John Nicholas, Elizabeth T. Bartom, Adam Grundhoff, Eva Gottwein
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	EBNA3C EBV HBZ HTLV-1 IRF4 KSHV Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a7cead49aba0468cb9441394698b0a5e
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spelling	oai:doaj.org-article:a7cead49aba0468cb9441394698b0a5e2021-11-15T15:56:44ZKaposi’s Sarcoma-Associated Herpesvirus Drives a Super-Enhancer-Mediated Survival Gene Expression Program in Primary Effusion Lymphoma10.1128/mBio.01457-202150-7511https://doaj.org/article/a7cead49aba0468cb9441394698b0a5e2020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01457-20https://doaj.org/toc/2150-7511ABSTRACT 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 oncogenic 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 cooperatively 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 oncogenic 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.Mark ManzanoThomas GüntherHyunwoo JuJohn NicholasElizabeth T. BartomAdam GrundhoffEva GottweinAmerican Society for MicrobiologyarticleEBNA3CEBVHBZHTLV-1IRF4KSHVMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	EBNA3C EBV HBZ HTLV-1 IRF4 KSHV Microbiology QR1-502
spellingShingle	EBNA3C EBV HBZ HTLV-1 IRF4 KSHV Microbiology QR1-502 Mark Manzano Thomas Günther Hyunwoo Ju John Nicholas Elizabeth T. Bartom Adam Grundhoff Eva Gottwein Kaposi’s Sarcoma-Associated Herpesvirus Drives a Super-Enhancer-Mediated Survival Gene Expression Program in Primary Effusion Lymphoma
description	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 oncogenic 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 cooperatively 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 oncogenic 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.
format	article
author	Mark Manzano Thomas Günther Hyunwoo Ju John Nicholas Elizabeth T. Bartom Adam Grundhoff Eva Gottwein
author_facet	Mark Manzano Thomas Günther Hyunwoo Ju John Nicholas Elizabeth T. Bartom Adam Grundhoff Eva Gottwein
author_sort	Mark Manzano
title	Kaposi’s Sarcoma-Associated Herpesvirus Drives a Super-Enhancer-Mediated Survival Gene Expression Program in Primary Effusion Lymphoma
title_short	Kaposi’s Sarcoma-Associated Herpesvirus Drives a Super-Enhancer-Mediated Survival Gene Expression Program in Primary Effusion Lymphoma
title_full	Kaposi’s Sarcoma-Associated Herpesvirus Drives a Super-Enhancer-Mediated Survival Gene Expression Program in Primary Effusion Lymphoma
title_fullStr	Kaposi’s Sarcoma-Associated Herpesvirus Drives a Super-Enhancer-Mediated Survival Gene Expression Program in Primary Effusion Lymphoma
title_full_unstemmed	Kaposi’s Sarcoma-Associated Herpesvirus Drives a Super-Enhancer-Mediated Survival Gene Expression Program in Primary Effusion Lymphoma
title_sort	kaposi’s sarcoma-associated herpesvirus drives a super-enhancer-mediated survival gene expression program in primary effusion lymphoma
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/a7cead49aba0468cb9441394698b0a5e
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Kaposi’s Sarcoma-Associated Herpesvirus Drives a Super-Enhancer-Mediated Survival Gene Expression Program in Primary Effusion Lymphoma

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