The downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 axis and by human cytomegalovirus (HCMV) associated factors allows the activation of the HCMV major IE promoter and the transition to productive infection

George Sourvinos; Antigoni Morou; Ioannis Sanidas; Ignea Codruta; Scott A Ezell; Christina Doxaki; Sotirios Kampranis; Filippos Kottakis; Philip N Tsichlis

doi:10.1371/journal.ppat.1004136

The downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 axis and by human cytomegalovirus (HCMV) associated factors allows the activation of the HCMV major IE promoter and the transition to productive infection

George Sourvinos, Antigoni Morou, Ioannis Sanidas, Ignea Codruta, Scott A Ezell, Christina Doxaki, Sotirios Kampranis, Filippos Kottakis, Philip N Tsichlis

11 Citationer (Scopus)

Abstract

Earlier studies had suggested that epigenetic mechanisms play an important role in the control of human cytomegalovirus (HCMV) infection. Here we show that productive HCMV infection is indeed under the control of histone H3K27 trimethylation. The histone H3K27 methyltransferase EZH2, and its regulators JARID2 and NDY1/KDM2B repress GFI1, a transcriptional repressor of the major immediate-early promoter (MIEP) of HCMV. Knocking down EZH2, NDY1/KDM2B or JARID2 relieves the repression and results in the upregulation of GFI1. During infection, the incoming HCMV rapidly downregulates the GFI1 mRNA and protein in both wild-type cells and in cells in which EZH2, NDY1/KDM2B or JARID2 were knocked down. However, since the pre-infection levels of GFI1 in the latter cells are significantly higher, the virus fails to downregulate it to levels permissive for MIEP activation and viral infection. Following the EZH2-NDY1/KDM2B-JARID2-independent downregulation of GFI1 in the early stages of infection, the virus also initiates an EZH2-NDY1/ΚDM2Β-JARID2-dependent program that represses GFI1 throughout the infection cycle. The EZH2 knockdown also delays histone H3K27 trimethylation in the immediate early region of HCMV, which is accompanied by a drop in H3K4 trimethylation that may contribute to the shEZH2-mediated repression of the major immediate early HCMV promoter. These data show that HCMV uses multiple mechanisms to allow the activation of the HCMV MIEP and to prevent cellular mechanisms from blocking the HCMV replication program.

Originalsprog	Engelsk
Tidsskrift	P L o S Pathogens
Vol/bind	10
Udgave nummer	5
Sider (fra-til)	e1004136
ISSN	1553-7366
DOI	https://doi.org/10.1371/journal.ppat.1004136
Status	Udgivet - maj 2014
Udgivet eksternt	Ja

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10.1371/journal.ppat.1004136

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Citationsformater

Sourvinos, G., Morou, A., Sanidas, I., Codruta, I., Ezell, S. A., Doxaki, C., Kampranis, S., Kottakis, F., & Tsichlis, P. N. (2014). The downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 axis and by human cytomegalovirus (HCMV) associated factors allows the activation of the HCMV major IE promoter and the transition to productive infection. P L o S Pathogens, 10(5), e1004136. https://doi.org/10.1371/journal.ppat.1004136

The downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 axis and by human cytomegalovirus (HCMV) associated factors allows the activation of the HCMV major IE promoter and the transition to productive infection. / Sourvinos, George; Morou, Antigoni; Sanidas, Ioannis et al.
I: P L o S Pathogens, Bind 10, Nr. 5, 05.2014, s. e1004136.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Sourvinos, G, Morou, A, Sanidas, I, Codruta, I, Ezell, SA, Doxaki, C, Kampranis, S, Kottakis, F & Tsichlis, PN 2014, 'The downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 axis and by human cytomegalovirus (HCMV) associated factors allows the activation of the HCMV major IE promoter and the transition to productive infection', P L o S Pathogens, bind 10, nr. 5, s. e1004136. https://doi.org/10.1371/journal.ppat.1004136

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title = "The downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 axis and by human cytomegalovirus (HCMV) associated factors allows the activation of the HCMV major IE promoter and the transition to productive infection",

abstract = "Earlier studies had suggested that epigenetic mechanisms play an important role in the control of human cytomegalovirus (HCMV) infection. Here we show that productive HCMV infection is indeed under the control of histone H3K27 trimethylation. The histone H3K27 methyltransferase EZH2, and its regulators JARID2 and NDY1/KDM2B repress GFI1, a transcriptional repressor of the major immediate-early promoter (MIEP) of HCMV. Knocking down EZH2, NDY1/KDM2B or JARID2 relieves the repression and results in the upregulation of GFI1. During infection, the incoming HCMV rapidly downregulates the GFI1 mRNA and protein in both wild-type cells and in cells in which EZH2, NDY1/KDM2B or JARID2 were knocked down. However, since the pre-infection levels of GFI1 in the latter cells are significantly higher, the virus fails to downregulate it to levels permissive for MIEP activation and viral infection. Following the EZH2-NDY1/KDM2B-JARID2-independent downregulation of GFI1 in the early stages of infection, the virus also initiates an EZH2-NDY1/ΚDM2Β-JARID2-dependent program that represses GFI1 throughout the infection cycle. The EZH2 knockdown also delays histone H3K27 trimethylation in the immediate early region of HCMV, which is accompanied by a drop in H3K4 trimethylation that may contribute to the shEZH2-mediated repression of the major immediate early HCMV promoter. These data show that HCMV uses multiple mechanisms to allow the activation of the HCMV MIEP and to prevent cellular mechanisms from blocking the HCMV replication program.",

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author = "George Sourvinos and Antigoni Morou and Ioannis Sanidas and Ignea Codruta and Ezell, {Scott A} and Christina Doxaki and Sotirios Kampranis and Filippos Kottakis and Tsichlis, {Philip N}",

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T1 - The downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 axis and by human cytomegalovirus (HCMV) associated factors allows the activation of the HCMV major IE promoter and the transition to productive infection

AU - Sourvinos, George

AU - Morou, Antigoni

AU - Sanidas, Ioannis

AU - Codruta, Ignea

AU - Ezell, Scott A

AU - Doxaki, Christina

AU - Kampranis, Sotirios

AU - Kottakis, Filippos

AU - Tsichlis, Philip N

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N2 - Earlier studies had suggested that epigenetic mechanisms play an important role in the control of human cytomegalovirus (HCMV) infection. Here we show that productive HCMV infection is indeed under the control of histone H3K27 trimethylation. The histone H3K27 methyltransferase EZH2, and its regulators JARID2 and NDY1/KDM2B repress GFI1, a transcriptional repressor of the major immediate-early promoter (MIEP) of HCMV. Knocking down EZH2, NDY1/KDM2B or JARID2 relieves the repression and results in the upregulation of GFI1. During infection, the incoming HCMV rapidly downregulates the GFI1 mRNA and protein in both wild-type cells and in cells in which EZH2, NDY1/KDM2B or JARID2 were knocked down. However, since the pre-infection levels of GFI1 in the latter cells are significantly higher, the virus fails to downregulate it to levels permissive for MIEP activation and viral infection. Following the EZH2-NDY1/KDM2B-JARID2-independent downregulation of GFI1 in the early stages of infection, the virus also initiates an EZH2-NDY1/ΚDM2Β-JARID2-dependent program that represses GFI1 throughout the infection cycle. The EZH2 knockdown also delays histone H3K27 trimethylation in the immediate early region of HCMV, which is accompanied by a drop in H3K4 trimethylation that may contribute to the shEZH2-mediated repression of the major immediate early HCMV promoter. These data show that HCMV uses multiple mechanisms to allow the activation of the HCMV MIEP and to prevent cellular mechanisms from blocking the HCMV replication program.

AB - Earlier studies had suggested that epigenetic mechanisms play an important role in the control of human cytomegalovirus (HCMV) infection. Here we show that productive HCMV infection is indeed under the control of histone H3K27 trimethylation. The histone H3K27 methyltransferase EZH2, and its regulators JARID2 and NDY1/KDM2B repress GFI1, a transcriptional repressor of the major immediate-early promoter (MIEP) of HCMV. Knocking down EZH2, NDY1/KDM2B or JARID2 relieves the repression and results in the upregulation of GFI1. During infection, the incoming HCMV rapidly downregulates the GFI1 mRNA and protein in both wild-type cells and in cells in which EZH2, NDY1/KDM2B or JARID2 were knocked down. However, since the pre-infection levels of GFI1 in the latter cells are significantly higher, the virus fails to downregulate it to levels permissive for MIEP activation and viral infection. Following the EZH2-NDY1/KDM2B-JARID2-independent downregulation of GFI1 in the early stages of infection, the virus also initiates an EZH2-NDY1/ΚDM2Β-JARID2-dependent program that represses GFI1 throughout the infection cycle. The EZH2 knockdown also delays histone H3K27 trimethylation in the immediate early region of HCMV, which is accompanied by a drop in H3K4 trimethylation that may contribute to the shEZH2-mediated repression of the major immediate early HCMV promoter. These data show that HCMV uses multiple mechanisms to allow the activation of the HCMV MIEP and to prevent cellular mechanisms from blocking the HCMV replication program.

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KW - Cells, Cultured

KW - Cytomegalovirus

KW - Cytomegalovirus Infections

KW - DNA-Binding Proteins

KW - Down-Regulation

KW - F-Box Proteins

KW - HEK293 Cells

KW - HeLa Cells

KW - Humans

KW - Immediate-Early Proteins

KW - Jumonji Domain-Containing Histone Demethylases

KW - Polycomb Repressive Complex 2

KW - Promoter Regions, Genetic

KW - Signal Transduction

KW - Transcription Factors

KW - Viral Proteins

KW - Virus Replication

U2 - 10.1371/journal.ppat.1004136

DO - 10.1371/journal.ppat.1004136

M3 - Journal article

C2 - 24830456

SN - 1553-7366

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SP - e1004136

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