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Open AccessArticle

Epigenetic Control of Cytomegalovirus Latency and Reactivation

by Xue-feng Liu, Xueqiong Wang, Shixian Yan, Zheng Zhang, Michael Abecassis and Mary Hummel

Viruses 2013, 5(5), 1325-1345; https://doi.org/10.3390/v5051325 - 23 May 2013

Cited by 38 | Viewed by 12255

Abstract

Cytomegalovirus (CMV) gene expression is repressed in latency due to heterochromatinization of viral genomes. In murine CMV (MCMV) latently infected mice, viral genomes are bound to histones with heterochromatic modifications, to enzymes that mediate these modifications, and to adaptor proteins that may recruit [...] Read more.

Cytomegalovirus (CMV) gene expression is repressed in latency due to heterochromatinization of viral genomes. In murine CMV (MCMV) latently infected mice, viral genomes are bound to histones with heterochromatic modifications, to enzymes that mediate these modifications, and to adaptor proteins that may recruit co-repressor complexes. Kinetic analyses of repressor binding show that these repressors are recruited at the earliest time of infection, suggesting that latency may be the default state. Kidney transplantation leads to epigenetic reprogramming of latent viral chromatin and reactivation of immediate early gene expression. Inflammatory signaling pathways, which activate transcription factors that regulate the major immediate early promoter (MIEP), likely mediate the switch in viral chromatin. Full article

(This article belongs to the Special Issue Chromatin Control of Viral Infection)

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Review

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2779 KiB

Open AccessReview

Chromatin Dynamics during Lytic Infection with Herpes Simplex Virus 1

by Kristen L. Conn and Luis M. Schang

Viruses 2013, 5(7), 1758-1786; https://doi.org/10.3390/v5071758 - 16 Jul 2013

Cited by 25 | Viewed by 8391

Abstract

Latent HSV-1 genomes are chromatinized with silencing marks. Since 2004, however, there has been an apparent inconsistency in the studies of the chromatinization of the HSV-1 genomes in lytically infected cells. Nuclease protection and chromatin immunoprecipitation assays suggested that the genomes were not [...] Read more.

Latent HSV-1 genomes are chromatinized with silencing marks. Since 2004, however, there has been an apparent inconsistency in the studies of the chromatinization of the HSV-1 genomes in lytically infected cells. Nuclease protection and chromatin immunoprecipitation assays suggested that the genomes were not regularly chromatinized, having only low histone occupancy. However, the chromatin modifications associated with transcribed and non-transcribed HSV-1 genes were those associated with active or repressed transcription, respectively. Moreover, the three critical HSV-1 transcriptional activators all had the capability to induce chromatin remodelling, and interacted with critical chromatin modifying enzymes. Depletion or overexpression of some, but not all, chromatin modifying proteins affected HSV-1 transcription, but often in unexpected manners. Since 2010, it has become clear that both cellular and HSV-1 chromatins are highly dynamic in infected cells. These dynamics reconcile the weak interactions between HSV-1 genomes and chromatin proteins, detected by nuclease protection and chromatin immunoprecipitation, with the proposed regulation of HSV-1 gene expression by chromatin, supported by the marks in the chromatin in the viral genomes and the abilities of the HSV-1 transcription activators to modulate chromatin. It also explains the sometimes unexpected results of interventions to modulate chromatin remodelling activities in infected cells. Full article

(This article belongs to the Special Issue Chromatin Control of Viral Infection)

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10505 KiB

Open AccessReview

Role of Polycomb Proteins in Regulating HSV-1 Latency

by Zachary Watson, Adit Dhummakupt, Harald Messer, Dane Phelan and David Bloom

Viruses 2013, 5(7), 1740-1757; https://doi.org/10.3390/v5071740 - 15 Jul 2013

Cited by 12 | Viewed by 8388

Abstract

Herpes simplex virus (HSV) establishes a latent infection within sensory neurons of humans. Latency is characterized by the transcriptional repression of lytic genes by the condensation of lytic gene regions into heterochromatin. Recent data suggest that facultative heterochromatin predominates, and that cellular Polycomb [...] Read more.

Herpes simplex virus (HSV) establishes a latent infection within sensory neurons of humans. Latency is characterized by the transcriptional repression of lytic genes by the condensation of lytic gene regions into heterochromatin. Recent data suggest that facultative heterochromatin predominates, and that cellular Polycomb proteins are involved in the establishment and maintenance of transcriptional repression during latency. This review summarizes these data and discusses the implication of viral and cellular factors in regulating heterochromatin composition. Full article

(This article belongs to the Special Issue Chromatin Control of Viral Infection)

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2196 KiB

Open AccessReview

Chromatin, Non-Coding RNAs, and the Expression of HIV

by Jessica N. Groen and Kevin V. Morris

Viruses 2013, 5(7), 1633-1645; https://doi.org/10.3390/v5071633 - 28 Jun 2013

Cited by 16 | Viewed by 8118

Abstract

HIV is a chronic viral infection affecting an estimated 34 million people worldwide. Current therapies employ the use of a cocktail of antiretroviral medications to reduce the spread and effects of HIV, however complete eradication from an individual currently remains unattainable. Viral latency [...] Read more.

HIV is a chronic viral infection affecting an estimated 34 million people worldwide. Current therapies employ the use of a cocktail of antiretroviral medications to reduce the spread and effects of HIV, however complete eradication from an individual currently remains unattainable. Viral latency and regulation of gene expression is a key consideration when developing effective treatments. While our understanding of these processes remains incomplete new developments suggest that non-coding RNA (ncRNA) mediated regulation may provide an avenue to controlling both viral expression and latency. Here we discuss the importance of known regulatory mechanisms and suggest directions for further study, in particular the use ncRNAs in controlling HIV expression. Full article

(This article belongs to the Special Issue Chromatin Control of Viral Infection)

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16327 KiB

Open AccessReview

Histone Deacetylases in Herpesvirus Replication and Virus-Stimulated Host Defense

by Amanda J. Guise, Hanna G. Budayeva, Benjamin A. Diner and Ileana M. Cristea

Viruses 2013, 5(7), 1607-1632; https://doi.org/10.3390/v5071607 - 27 Jun 2013

Cited by 30 | Viewed by 10917

Abstract

Emerging evidence highlights a critical role for protein acetylation during herpesvirus infection. As prominent modulators of protein acetylation, histone deacetylases (HDACs) are essential transcriptional and epigenetic regulators. Not surprisingly, viruses have evolved a wide array of mechanisms to subvert HDAC functions. Here, we [...] Read more.

Emerging evidence highlights a critical role for protein acetylation during herpesvirus infection. As prominent modulators of protein acetylation, histone deacetylases (HDACs) are essential transcriptional and epigenetic regulators. Not surprisingly, viruses have evolved a wide array of mechanisms to subvert HDAC functions. Here, we review the mechanisms underlying HDAC regulation during herpesvirus infection. We next discuss the roles of acetylation in host defense against herpesvirus infection. Finally, we provide a perspective on the contribution of current mass spectrometry-based “omic” technologies to infectious disease research, offering a systems biology view of infection. Full article

(This article belongs to the Special Issue Chromatin Control of Viral Infection)

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2056 KiB

Open AccessReview

Bromodomain Proteins in HIV Infection

by Daniela Boehm, Ryan J. Conrad and Melanie Ott

Viruses 2013, 5(6), 1571-1586; https://doi.org/10.3390/v5061571 - 21 Jun 2013

Cited by 33 | Viewed by 11246

Abstract

Bromodomains are conserved protein modules of ~110 amino acids that bind acetylated lysine residues in histone and non-histone proteins. Bromodomains are present in many chromatin-associated transcriptional regulators and have been linked to diverse aspects of the HIV life cycle, including transcription and integration. [...] Read more.

Bromodomains are conserved protein modules of ~110 amino acids that bind acetylated lysine residues in histone and non-histone proteins. Bromodomains are present in many chromatin-associated transcriptional regulators and have been linked to diverse aspects of the HIV life cycle, including transcription and integration. Here, we review the role of bromodomain-containing proteins in HIV infection. We begin with a focus on acetylated viral factors, followed by a discussion of structural and biological studies defining the involvement of bromodomain proteins in the HIV life cycle. We end with an overview of promising new studies of bromodomain inhibitory compounds for the treatment of HIV latency. Full article

(This article belongs to the Special Issue Chromatin Control of Viral Infection)

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653 KiB

Open AccessReview

The Role of Chromatin in Adenoviral Vector Function

by Carmen M. Wong, Emily R. McFall, Joseph K. Burns and Robin J. Parks

Viruses 2013, 5(6), 1500-1515; https://doi.org/10.3390/v5061500 - 14 Jun 2013

Cited by 15 | Viewed by 7178

Abstract

Vectors based on adenovirus (Ad) are one of the most commonly utilized platforms for gene delivery to cells in molecular biology studies and in gene therapy applications. Ad is also the most popular vector system in human clinical gene therapy trials, largely due [...] Read more.

Vectors based on adenovirus (Ad) are one of the most commonly utilized platforms for gene delivery to cells in molecular biology studies and in gene therapy applications. Ad is also the most popular vector system in human clinical gene therapy trials, largely due to its advantageous characteristics such as high cloning capacity (up to 36 kb), ability to infect a wide variety of cell types and tissues, and relative safety due to it remaining episomal in transduced cells. The latest generation of Ad vectors, helper‑dependent Ad (hdAd), which are devoid of all viral protein coding sequences, can mediate high-level expression of a transgene for years in a variety of species ranging from rodents to non-human primates. Given the importance of histones and chromatin in modulating gene expression within the host cell, it is not surprising that Ad, a nuclear virus, also utilizes these proteins to protect the genome and modulate virus- or vector‑encoded genes. In this review, we will discuss our current understanding of the contribution of chromatin to Ad vector function. Full article

(This article belongs to the Special Issue Chromatin Control of Viral Infection)

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8182 KiB

Open AccessReview

Regulation of Human Cytomegalovirus Transcription in Latency: Beyond the Major Immediate-Early Promoter

by Matthew Reeves and John Sinclair

Viruses 2013, 5(6), 1395-1413; https://doi.org/10.3390/v5061395 - 3 Jun 2013

Cited by 35 | Viewed by 9408

Abstract

Lytic infection of differentiated cell types with human cytomegalovirus (HCMV) results in the temporal expression of between 170–200 open reading frames (ORFs). A number of studies have demonstrated the temporal regulation of these ORFs and that this is orchestrated by both viral and [...] Read more.

Lytic infection of differentiated cell types with human cytomegalovirus (HCMV) results in the temporal expression of between 170–200 open reading frames (ORFs). A number of studies have demonstrated the temporal regulation of these ORFs and that this is orchestrated by both viral and cellular mechanisms associated with the co-ordinated recruitment of transcription complexes and, more recently, higher order chromatin structure. Importantly, HCMV, like all herpes viruses, establishes a lifelong latent infection of the host—one major site of latency being the undifferentiated haematopoietic progenitor cells resident in the bone marrow. Crucially, the establishment of latency is concomitant with the recruitment of cellular enzymes that promote extensive methylation of histones bound to the major immediate early promoter. As such, the repressive chromatin structure formed at the major immediate early promoter (MIEP) elicits inhibition of IE gene expression and is a major factor involved in maintenance of HCMV latency. However, it is becoming increasingly clear that a distinct subset of viral genes is also expressed during latency. In this review, we will discuss the mechanisms that control the expression of these latency-associated transcripts and illustrate that regulation of these latency-associated promoters is also subject to chromatin mediated regulation and that the instructive observations previously reported regarding the negative regulation of the MIEP during latency are paralleled in the regulation of latent gene expression. Full article

(This article belongs to the Special Issue Chromatin Control of Viral Infection)

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719 KiB

Open AccessReview

Current Understanding of the Role of the Brd4 Protein in the Papillomavirus Lifecycle

by Alison A. McBride and Moon Kyoo Jang

Viruses 2013, 5(6), 1374-1394; https://doi.org/10.3390/v5061374 - 30 May 2013

Cited by 38 | Viewed by 11811

Abstract

The Brd4 protein is an epigenetic reader that is central to regulation of cellular transcription and mitotic bookmarking. The transcription and replication proteins of many viruses interact with Brd4. We describe the multiple roles of Brd4 in the papillomavirus lifecycle. Full article

(This article belongs to the Special Issue Chromatin Control of Viral Infection)

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896 KiB

Open AccessReview

The Chromatin Landscape of Kaposi’s Sarcoma-Associated Herpesvirus

by Zsolt Toth, Kevin Brulois and Jae U. Jung

Viruses 2013, 5(5), 1346-1373; https://doi.org/10.3390/v5051346 - 23 May 2013

Cited by 57 | Viewed by 10936

Abstract

Kaposi’s sarcoma-associated herpesvirus is an oncogenic γ-herpesvirus that causes latent infection in humans. In cells, the viral genome adopts a highly organized chromatin structure, which is controlled by a wide variety of cellular and viral chromatin regulatory factors. In the past few years, [...] Read more.

Kaposi’s sarcoma-associated herpesvirus is an oncogenic γ-herpesvirus that causes latent infection in humans. In cells, the viral genome adopts a highly organized chromatin structure, which is controlled by a wide variety of cellular and viral chromatin regulatory factors. In the past few years, interrogation of the chromatinized KSHV genome by whole genome-analyzing tools revealed that the complex chromatin landscape spanning the viral genome in infected cells has important regulatory roles during the viral life cycle. This review summarizes the most recent findings regarding the role of histone modifications, histone modifying enzymes, DNA methylation, microRNAs, non-coding RNAs and the nuclear organization of the KSHV epigenome in the regulation of latent and lytic viral gene expression programs as well as their connection to KSHV-associated pathogenesis. Full article

(This article belongs to the Special Issue Chromatin Control of Viral Infection)

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Open AccessReview

The Dynamics of HCF-1 Modulation of Herpes Simplex Virus Chromatin during Initiation of Infection

by Jodi L. Vogel and Thomas M. Kristie

Viruses 2013, 5(5), 1272-1291; https://doi.org/10.3390/v5051272 - 22 May 2013

Cited by 34 | Viewed by 10988

Abstract

Successful infection of herpes simplex virus is dependent upon chromatin modulation by the cellular coactivator host cell factor-1 (HCF-1). This review focuses on the multiple chromatin modulation components associated with HCF-1 and the chromatin-related dynamics mediated by this coactivator that lead to the [...] Read more.

Successful infection of herpes simplex virus is dependent upon chromatin modulation by the cellular coactivator host cell factor-1 (HCF-1). This review focuses on the multiple chromatin modulation components associated with HCF-1 and the chromatin-related dynamics mediated by this coactivator that lead to the initiation of herpes simplex virus (HSV) immediate early gene expression. Full article

(This article belongs to the Special Issue Chromatin Control of Viral Infection)

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Open AccessReview

Biochemical and Functional Interactions of Human Papillomavirus Proteins with Polycomb Group Proteins

by Margaret E. McLaughlin-Drubin and Karl Munger

Viruses 2013, 5(5), 1231-1249; https://doi.org/10.3390/v5051231 - 14 May 2013

Cited by 28 | Viewed by 10181

Abstract

The role of enzymes involved in polycomb repression of gene transcription has been studied extensively in human cancer. Polycomb repressive complexes mediate oncogene-induced senescence, a principal innate cell-intrinsic tumor suppressor pathway that thwarts expansion of cells that have suffered oncogenic hits. Infections with [...] Read more.

The role of enzymes involved in polycomb repression of gene transcription has been studied extensively in human cancer. Polycomb repressive complexes mediate oncogene-induced senescence, a principal innate cell-intrinsic tumor suppressor pathway that thwarts expansion of cells that have suffered oncogenic hits. Infections with human cancer viruses including human papillomaviruses (HPVs) and Epstein-Barr virus can trigger oncogene-induced senescence, and the viruses have evolved strategies to abrogate this response in order to establish an infection and reprogram their host cells to establish a long-term persistent infection. As a consequence of inhibiting polycomb repression and evading oncogene induced-senescence, HPV infected cells have an altered epigenetic program as evidenced by aberrant homeobox gene expression. Similar alterations are frequently observed in non-virus associated human cancers and may be harnessed for diagnosis and therapy. Full article

(This article belongs to the Special Issue Chromatin Control of Viral Infection)

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298 KiB

Open AccessReview

The Role of the CoREST/REST Repressor Complex in Herpes Simplex Virus 1 Productive Infection and in Latency

by Guoying Zhou, Te Du and Bernard Roizman

Viruses 2013, 5(5), 1208-1218; https://doi.org/10.3390/v5051208 - 29 Apr 2013

Cited by 23 | Viewed by 8665

Abstract

REST is a key component of the HDAC1 or 2, CoREST, LSD1, REST (HCLR) repressor complex. The primary function of the HCLR complex is to silence neuronal genes in non-neuronal cells. HCLR plays a role in regulating the expression of viral genes in [...] Read more.

REST is a key component of the HDAC1 or 2, CoREST, LSD1, REST (HCLR) repressor complex. The primary function of the HCLR complex is to silence neuronal genes in non-neuronal cells. HCLR plays a role in regulating the expression of viral genes in productive infections as a donor of LDS1 for expression of α genes and as a repressor of genes expressed later in infection. In sensory neurons the HCLR complex is involved in the silencing of viral genome in the course of establishment of latency. The thesis of this article is that (a) sensory neurons evolved a mechanism to respond to the presence and suppress the transmission of infectious agents from the periphery to the CNS and (b) HSV evolved subservience to the HCLR with at least two objectives: to maintain a level of replication consistent with maximal person-to-person spread and to enable it to take advantage of neuronal innate immune responses to survive and be available for reactivation shielded from adaptive immune responses of the host. Full article

(This article belongs to the Special Issue Chromatin Control of Viral Infection)

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Open AccessReview

Deregulation of Epigenetic Mechanisms by the Hepatitis B Virus X Protein in Hepatocarcinogenesis

by Ourania M. Andrisani

Viruses 2013, 5(3), 858-872; https://doi.org/10.3390/v5030858 - 18 Mar 2013

Cited by 27 | Viewed by 8573

Abstract

This review focuses on the significance of deregulation of epigenetic mechanisms by the hepatitis B virus (HBV) X protein in hepatocarcinogenesis and HBV replication. Epigenetic mechanisms, DNA methylation, and specific histone modifications, e.g., trimethylation of H3 on lysine-27 or lysine-4, maintain ‘cellular memory’ [...] Read more.

This review focuses on the significance of deregulation of epigenetic mechanisms by the hepatitis B virus (HBV) X protein in hepatocarcinogenesis and HBV replication. Epigenetic mechanisms, DNA methylation, and specific histone modifications, e.g., trimethylation of H3 on lysine-27 or lysine-4, maintain ‘cellular memory’ by silencing expression of lineage-inducing factors in stem cells and conversely, of pluripotency factors in differentiated cells. The X protein has been reported to induce expression of DNA methyltransferases (DNMTs), likely promoting epigenetic changes during hepatocarcinogenesis. Furthermore, in cellular and animal models of X-mediated oncogenic transformation, protein levels of chromatin modifying proteins Suz12 and Znf198 are down-regulated. Suz12 is essential for the Polycomb Repressive Complex 2 (PRC2) mediating the repressive trimethylation of H3 on lysine-27 (H3K27me3). Znf198, stabilizes the LSD1-CoREST-HDAC complex that removes, via lysine demethylase1 (LSD1), the activating trimethylation of H3 on lysine-4 (H3K4me3). Down-regulation of Suz12 also occurs in liver tumors of woodchucks chronically infected by woodchuck hepatitis virus, an animal model recapitulating HBV-mediated hepatocarcinogenesis in humans. Significantly, subgroups of HBV-induced liver cancer re-express hepatoblast and fetal markers, and imprinted genes, suggesting hepatocyte reprogramming during oncogenic transformation. Lastly, down-regulation of Suz12 and Znf198 enhances HBV replication. Collectively, these observations suggest deregulation of epigenetic mechanisms by HBV X protein influences both the viral cycle and the host cell. Full article

(This article belongs to the Special Issue Chromatin Control of Viral Infection)

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