Human tumor viruses: induction of three-dimensional alterations in the host genome structure

Minarovits, Janos

doi:10.3389/fmicb.2023.1280210

“…The EBV genome is epigenetically programmed upon B cell infection [ 7 – 10 ]. While EBV genomic DNA is epigenetically naïve in viral particles, it is rapidly chromatinized as incoming viral genomes reach the infected cell nucleus [ 7 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Germinal center cytokine driven epigenetic control of Epstein-Barr virus latency gene expression

Liao,

Yan,

Beri

et al. 2024

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Epstein-Barr virus (EBV) persistently infects 95% of adults worldwide and is associated with multiple human lymphomas that express characteristic EBV latency programs used by the virus to navigate the B-cell compartment. Upon primary infection, the EBV latency III program, comprised of six Epstein-Barr Nuclear Antigens (EBNA) and two Latent Membrane Protein (LMP) antigens, drives infected B-cells into germinal center (GC). By incompletely understood mechanisms, GC microenvironmental cues trigger the EBV genome to switch to the latency II program, comprised of EBNA1, LMP1 and LMP2A and observed in GC-derived Hodgkin lymphoma. To gain insights into pathways and epigenetic mechanisms that control EBV latency reprogramming as EBV-infected B-cells encounter microenvironmental cues, we characterized GC cytokine effects on EBV latency protein expression and on the EBV epigenome. We confirmed and extended prior studies highlighting GC cytokine effects in support of the latency II transition. The T-follicular helper cytokine interleukin 21 (IL-21), which is a major regulator of GC responses, and to a lesser extent IL-4 and IL-10, hyper-induced LMP1 expression, while repressing EBNA expression. However, follicular dendritic cell cytokines including IL-15 and IL-27 downmodulate EBNA but not LMP1 expression. CRISPR editing highlighted that STAT3 and STAT5 were necessary for cytokine mediated EBNA silencing via epigenetic effects at the EBV genomic C promoter. By contrast, STAT3 was instead necessary for LMP1 promoter epigenetic remodeling, including gain of activating histone chromatin marks and loss of repressive polycomb repressive complex silencing marks. Thus, EBV has evolved to coopt STAT signaling to oppositely regulate the epigenetic status of key viral genomic promoters in response to GC cytokine cues.

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“…The EBV genome is epigenetically programmed upon B cell infection. [7][8][9][10] While EBV genomic DNA is epigenetically naïve in viral particles, it is rapidly chromatinized as incoming viral genomes reach the infected cell nucleus. 7,11 Histone epigenetic marks, DNA methylation and three dimensional EBV genomic architecture then serve as major regulators of EBV gene expression.…”

Section: Introductionmentioning

confidence: 99%

Germinal Center Cytokines Driven Epigenetic Control of Epstein-Barr Virus Latency Gene Expression

Liao,

Yan,

Beri

et al. 2024

Preprint

0

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Epstein-Barr virus (EBV) persistently infects 95% of adults worldwide and is associated with multiple human lymphomas that express characteristic EBV latency programs used by the virus to navigate the B-cell compartment. Upon primary infection, the EBV latency III program, comprised of six Epstein-Barr Nuclear Antigens (EBNA) and two Latent Membrane Protein (LMP) antigens, drives infected B-cells into germinal center (GC). By incompletely understood mechanisms, GC microenvironmental cues trigger the EBV genome to switch to the latency II program, comprised of EBNA1, LMP1 and LMP2A and observed in GC-derived Hodgkin lymphoma. To gain insights into pathways and epigenetic mechanisms that control EBV latency reprogramming as EBV-infected B-cells encounter microenvironmental cues, we characterized GC cytokine effects on EBV latency protein expression and on the EBV epigenome. We confirmed and extended prior studies highlighting GC cytokine effects in support of the latency II transition. The T-follicular helper cytokine interleukin 21 (IL-21), which is a major regulator of GC responses, and to a lesser extent IL-4 and IL-10, hyper-induced LMP1 expression, while repressing EBNA expression. However, follicular dendritic cell cytokines including IL-15 and IL-27 downmodulate EBNA but not LMP1 expression.CRISPR editing highlighted that STAT3 and STAT5 were necessary for cytokine mediated EBNA silencing via epigenetic effects at the EBV genomic C promoter. By contrast, STAT3 was instead necessary for LMP1 promoter epigenetic remodeling, including gain of activating histone chromatin marks and loss of repressive polycomb repressive complex silencing marks. Thus, EBV has evolved to coopt STAT signaling to oppositely regulate the epigenetic status of key viral genomic promoters in response to GC cytokine cues.Author SummaryA longstanding question has remained how Epstein-Barr virus (EBV) epigenetically switches between latency programs as it navigates the B-cell compartment. EBV uses its latency III program to stimulate newly infected B cell growth and then trafficking into secondary lymphoid tissue germinal centers (GC). In latency III, the viral C promoter stimulates expression of six Epstein-Barr nuclear antigens (EBNA) that in turn induce two latent membrane proteins (LMP). However, knowledge has remained incomplete about how GC microenvironmental cues trigger switching to latency II, where only one EBNA and two LMP are expressed, a program observed in Hodgkin lymphoma. Building on prior evidence that GC cytokines are a major cue, we systematically tested effects of cytokines secreted by GC-resident T follicular helper and follicular dendritic cells on EBV latency gene expression and on epigenetic remodeling of their promoters. This highlighted that a range of GC cytokines repress latency III EBNA, while only several support LMP1 expression, major events in the transition between the latency III and II programs. We identified key downstream roles of JAK/STAT signaling in relaying cytokine signals to the EBV epigenome, including obligatory STAT3 and 5 roles in rewiring of C and LMP promoter histone epigenetic marks.

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Introduction: The Role of Pathogens Associated with Human Cancer and the Concept of Omics–An Overview

Velázquez-Márquez,

Huelgas-Saavedra

2024

Pathogens Associated With the Development of Cancer in Humans

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Human tumor viruses: induction of three-dimensional alterations in the host genome structure

Cited by 4 publications

References 40 publications

Germinal center cytokine driven epigenetic control of Epstein-Barr virus latency gene expression

Germinal center cytokine driven epigenetic control of Epstein-Barr virus latency gene expression

Germinal Center Cytokines Driven Epigenetic Control of Epstein-Barr Virus Latency Gene Expression

Introduction: The Role of Pathogens Associated with Human Cancer and the Concept of Omics–An Overview

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