Biphasic Recruitment of Transcriptional Repressors to the Murine Cytomegalovirus Major Immediate-Early Promoter during the Course of Infection
            <i>In Vivo</i>

Liu, Xue Feng; Yan, Shi; Abecassis, Michael; Hummel, Mary

doi:10.1128/jvi.02380-09

Cited by 23 publications

(48 citation statements)

References 82 publications

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“…CMV genomes are heterochromatinized and the IE genes, which are required for lytic replication, are transcriptionally silent in latent infection (Grzimek et al, 2001;Hummel et al, 2001;Kurz et al, 1997Kurz et al, , 1999Liu et al, 2008Liu et al, , 2010Seckert et al, 2013;Simon et al, 2005). Activation of IE gene expression, through recruitment of transcription factors that control MIEP activity and remodelling of viral chromatin, is therefore likely required for reactivation of the virus.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the very low MCMV DNA copy number in kidneys of latent mice [*1 copy of MCMV DNA per 10 000 cellular genomes (Li et al, 2012)] and the large amount of chromatin required for each ChIP, chromatin from 5-6 kidneys was pooled for each antibody. Frozen pellets of fixed tissue from 30-50 transplants were resuspended in hypotonic lysis buffer, and processed for immunoprecipitation as previously described (Liu et al, 2008(Liu et al, , 2010. Ten per cent of the chromatin was removed for analysis of input DNA.…”

Section: Methodsmentioning

confidence: 99%

“…Ten per cent of the chromatin was removed for analysis of input DNA. The remaining chromatin was pre-cleared with IgG and incubated overnight at 4 uC with antibodies against target proteins as previously described (Liu et al, 2008(Liu et al, , 2010. The following antibodies were used: NF-k Bp65 (Abcam, Ab7970-1), NF-k Bp50 (Abcam Ab7971), junD (SantaCruz Biotech, sc-74x) and actin (SantaCruz Biotech,.…”

Section: Methodsmentioning

confidence: 99%

“…The contralateral donor kidneys were removed at the time of the transplant for use as latent controls. Fresh tissue was finely minced on ice, and the chromatin was fixed in 1 % formaldehyde as previously described (Liu et al, 2008(Liu et al, , 2010, and frozen in liquid nitrogen. Due to the very low MCMV DNA copy number in kidneys of latent mice [*1 copy of MCMV DNA per 10 000 cellular genomes (Li et al, 2012)] and the large amount of chromatin required for each ChIP, chromatin from 5-6 kidneys was pooled for each antibody.…”

Section: Methodsmentioning

confidence: 99%

“…The following antibodies were used: NF-k Bp65 (Abcam, Ab7970-1), NF-k Bp50 (Abcam Ab7971), junD (SantaCruz Biotech, sc-74x) and actin (SantaCruz Biotech,. qPCR analysis to quantify input and immunoprecipitated DNA were performed as previously described (Liu et al, 2008(Liu et al, , 2010.…”

Section: Methodsmentioning

confidence: 99%

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Transplant-induced reactivation of murine cytomegalovirus immediate early gene expression is associated with recruitment of NF-κB and AP-1 to the major immediate early promoter

Liu

Jie

Zhang

et al. 2016

Journal of General Virology

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Reactivation of latent human cytomegalovirus is a significant infectious complication of organ transplantation and current therapies target viral replication once reactivation of latent virus has already occurred. The specific molecular pathways that activate viral gene expression in response to transplantation are not well understood. Our studies aim to identify these factors, with the goal of developing novel therapies that prevent transcriptional reactivation in transplant recipients. Murine cytomegalovirus (MCMV) is a valuable model for studying latency and reactivation of CMV in vivo. We previously demonstrated that transplantation of MCMV-latently infected kidneys into allogeneic recipients induces reactivation of immediate early (IE) gene expression and epigenetic reprogramming of the major immediate early promoter (MIEP) within 48 h. We hypothesize that these events are mediated by activation of signalling pathways that lead to binding of transcription factors to the MIEP, including AP-1 and NF-k B. Here we show that transplantation induces rapid activation of several members of the AP-1 and NF-k B transcription factor family and we demonstrate that canonical NF-k B (p65/p50), the junD component of AP-1, and nucleosome remodelling complexes are recruited to the MIEP following transplantation. Proteomic analysis of recipient plasma and transcriptome analysis of kidney RNA identified five extracellular ligands, including TNF, IL-1b, IL-18, CD40L and IL-6, and three intracellular signalling pathways associated with reactivation of IE gene expression. Identification of the factors that mediate activation of these signalling pathways may eventually lead to new therapies to prevent reactivation of CMV and its sequelae.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Transplant-induced reactivation of murine cytomegalovirus immediate early gene expression is associated with recruitment of NF-κB and AP-1 to the major immediate early promoter

Liu

Jie

Zhang

et al. 2016

Journal of General Virology

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Aberrant fetal macrophage/microglial reactions to cytomegalovirus infection

Sakao-Suzuki

Kawasaki

Akamatsu

et al. 2014

Ann Clin Transl Neurol

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ObjectiveCongenital cytomegalovirus (CMV) infection is the leading viral cause of neurodevelopmental disorders in humans, with the most severe and permanent sequelae being those affecting the cerebrum. As the fetal immune reactions to congenital CMV infection in the brain and their effects on cerebral development remain elusive, our aim was to investigate primitive innate immunity to CMV infection and its effects on cerebral corticogenesis in a mouse model for congenital CMV infection using a precise intraplacental inoculation method.MethodsAt 13.5 embryonic days (E13.5), pregnant C57BL/6 mice were intraplacentally infected with murine CMV (MCMV). Placentas and fetal organs were collected at 1, 3, and 5 days postinfection and analyzed.ResultsMCMV antigens were found frequently in perivascular macrophages, and subsequently in neural stem/progenitor cells (NSPCs). With increased expression of inducible nitric oxide synthase and proinflammatory cytokines, activated macrophages infiltrated into the infectious foci. In addition to the infected area, the numbers of both meningeal macrophages and parenchymal microglia increased even in the uninfected areas of MCMV-infected brain due to recruitment of their precursors from other sites. A bromodeoxyuridine (BrdU) incorporation experiment demonstrated that MCMV infection globally disrupted the self-renewal of NSPCs. Furthermore, BrdU-labeled neurons, particularly Brn2+ neurons of upper layers II/III in the cortical plate, decreased in number significantly in the MCMV-infected E18.5 cerebrum.InterpretationBrain macrophages are crucial for innate immunity during MCMV infection in the fetal brain, while their aberrant recruitment and activation may adversely impact on the stemness of NSPCs, resulting in neurodevelopmental disorders.

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How to control an infectious bead string: nucleosome‐based regulation and targeting of herpesvirus chromatin

Nevels

Nitzsche

Paulus

2011

Reviews in Medical Virology

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Herpesvirus infections of humans can cause a broad variety of symptoms ranging from mild afflictions to life-threatening disease. During infection, the large double-stranded DNA genomes of all herpesviruses are transcribed, replicated and encapsidated in the host cell nucleus, where DNA is typically structured and manoeuvred through nucleosomes. Nucleosomes individually assemble DNA around core histone octamers to form 'beads-on-a-string' chromatin fibres. Herpesviruses have responded to the advantages and challenges of chromatin formation in biologically unique ways. Although herpesvirus DNA is devoid of histones within nucleocapsids, nuclear viral genomes most likely form irregularly arranged or unstable nucleosomes during productive infection, and regular nucleosomal arrays resembling host cell chromatin in latently infected cells. Besides variations in nucleosome density, herpesvirus chromatin 'bead strings' undergo dynamic changes in histone composition and modification during the different stages of productive replication, latent infection and reactivation from latency, raising the likely possibility that epigenetic processes may dictate, at least in part, the outcome of infection and ensuing pathogenesis. Here, we summarise and discuss several new and important aspects regarding the nucleosome-based mechanisms that regulate herpesvirus chromatin structure and function in infected cells. Special emphasis is given to processes of histone deposition, histone variant exchange and covalent histone modification in relation to the transcription from the viral genome during productive and latent infections by human cytomegalovirus and herpes simplex virus type 1. We also present an overview on emerging histone-directed antiviral strategies that may be developed into 'epigenetic therapies' to improve current prevention and treatment options targeting herpesvirus infection and disease.

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Biphasic Recruitment of Transcriptional Repressors to the Murine Cytomegalovirus Major Immediate-Early Promoter during the Course of Infection In Vivo

Cited by 23 publications

References 82 publications

Transplant-induced reactivation of murine cytomegalovirus immediate early gene expression is associated with recruitment of NF-κB and AP-1 to the major immediate early promoter

Transplant-induced reactivation of murine cytomegalovirus immediate early gene expression is associated with recruitment of NF-κB and AP-1 to the major immediate early promoter

Aberrant fetal macrophage/microglial reactions to cytomegalovirus infection

How to control an infectious bead string: nucleosome‐based regulation and targeting of herpesvirus chromatin

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