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.
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.
Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America; Laboratory of Virology, Medical School, University of Crete, Heraklion, Crete, Greece.
George
G
Sourvinos
Laboratory of Virology, Medical School, University of Crete, Heraklion, Crete, Greece.
Antigoni
A
Morou
Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.
Ioannis
I
Sanidas
Laboratory of Biochemistry, Medical School, University of Crete, Heraklion, Crete, Greece.
Ignea
I
Codruta
Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.
Scott A
SA
Ezell
Laboratory of Biochemistry, Medical School, University of Crete, Heraklion, Crete, Greece.
Christina
C
Doxaki
Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America; Laboratory of Biochemistry, Medical School, University of Crete, Heraklion, Crete, Greece.
Sotirios C
SC
Kampranis
Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.
Filippos
F
Kottakis
Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.
Philip N
PN
Tsichlis
D000956:Antigens, Viral / Q000235:genetics; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000821:virology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D044783:F-Box Proteins / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D056484:Jumonji Domain-Containing Histone Demethylases / Q000502:physiology*; D063151:Polycomb Repressive Complex 2 / Q000502:physiology*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology; D014779:Virus Replication / Q000235:genetics
D000956:Antigens, Viral; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; C498275:GFI1 protein, human; D017874:Immediate-Early Proteins; C547777:JARID2 protein, human; D014157:Transcription Factors; D014764:Viral Proteins; C044582:immediate-early proteins, cytomegalovirus; D056484:Jumonji Domain-Containing Histone Demethylases; C524747:Kdm2b protein, mouse; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2