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 Citations (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.

Original language	English
Journal	P L o S Pathogens
Volume	10
Issue number	5
Pages (from-to)	e1004136
ISSN	1553-7366
DOIs	https://doi.org/10.1371/journal.ppat.1004136
Publication status	Published - May 2014
Externally published	Yes

Keywords

Antigens, Viral
Cells, Cultured
Cytomegalovirus
Cytomegalovirus Infections
DNA-Binding Proteins
Down-Regulation
F-Box Proteins
HEK293 Cells
HeLa Cells
Humans
Immediate-Early Proteins
Jumonji Domain-Containing Histone Demethylases
Polycomb Repressive Complex 2
Promoter Regions, Genetic
Signal Transduction
Transcription Factors
Viral Proteins
Virus Replication

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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.
In: P L o S Pathogens, Vol. 10, No. 5, 05.2014, p. e1004136.

Research output: Contribution to journal › Journal article › Research › 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, vol. 10, no. 5, pp. e1004136. https://doi.org/10.1371/journal.ppat.1004136

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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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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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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 - 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

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