Profiling of immune related genes silenced in EBV-positive gastric carcinoma identified novel restriction factors of human gammaherpesviruses

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Abstract

EBV-associated gastric cancer (EBVaGC) is characterized by high frequency of DNA methylation. In this study, we investigated how epigenetic alteration of host genome contributes to pathogenesis of EBVaGC through the analysis of transcriptomic and epigenomic datasets from NIH TCGA (The Cancer Genome Atlas) consortium. We identified that immune related genes (IRGs) is a group of host genes preferentially silenced in EBV-positive gastric cancers through DNA hypermethylation. Further functional characterizations of selected IRGs reveal their novel antiviral activity against not only EBV but also KSHV. In particular, we showed that metallothionein-1 (MT1) and homeobox A (HOXA) gene clusters are down-regulated via EBV-driven DNA hypermethylation. Several MT1 isoforms suppress EBV lytic replication and release of progeny virions as well as KSHV lytic reactivation, suggesting functional redundancy of these genes. In addition, single HOXA10 isoform exerts antiviral activity against both EBV and KSHV. We also confirmed the antiviral effect of other dysregulated IRGs, such as IRAK2 and MAL, in scenario of EBV and KSHV lytic reactivation. Collectively, our results demonstrated that epigenetic silencing of IRGs is a viral strategy to escape immune surveillance and promote viral propagation, which is overall beneficial to viral oncogenesis of human gamma-herpesviruses (EBV and KSHV), considering that these IRGs possess antiviral activities against these oncoviruses.

Author summary

Epstein-Barr virus (EBV), one of the human gamma-herpesviruses, is a well-defined viral agent that strongly associates with malignancies of lymphoid and epithelial origin. EBV-associated gastric carcinoma (EBVaGC) is the most common malignancy caused by EBV infection. In this paper, we identified that beyond tumor suppressor genes, immune related genes (IRGs) are another group of host genes that are extensively DNA hypermethylated and epigenetically silenced in EBVaGC comparing to non-EBV GC. For certain IRGs, such as metallothionein-1 (MT1) and homeobox A (HOXA) genes, the whole gene clusters undergo DNA hypermethylation in EBVaGC, while it also occurs for isolated individual IRGs, such as IRAK2 and MAL. Considering the critical role of innate immunity in antiviral control, we expected that silencing of IRGs would benefit EBV viral replication and propagation. Indeed, our further investigation of several IRGs (MT1G, HOXA10, IRAK2, and MAL) confirmed their antiviral activities against EBV lytic replication. Some of them also suppress lytic replication of another human gamma-herpesvirus, Kaposi’s sarcoma-associated herpesvirus (KSHV), indicating their broad antiviral spectrum. Collectively, our results demonstrated that epigenetic silencing of antiviral IRGs is an efficient viral strategy utilized by oncoviruses, such as EBV, to escape immune surveillance and promote viral propagation, which is overall beneficial to viral oncogenesis.

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Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells.

Michael Weber, Jonathan J Davies, David Wittig … (2005)

Cytosine methylation is required for mammalian development and is often perturbed in human cancer. To determine how this epigenetic modification is distributed in the genomes of primary and transformed cells, we used an immunocapturing approach followed by DNA microarray analysis to generate methylation profiles of all human chromosomes at 80-kb resolution and for a large set of CpG islands. In primary cells we identified broad genomic regions of differential methylation with higher levels in gene-rich neighborhoods. Female and male cells had indistinguishable profiles for autosomes but differences on the X chromosome. The inactive X chromosome (Xi) was hypermethylated at only a subset of gene-rich regions and, unexpectedly, overall hypomethylated relative to its active counterpart. The chromosomal methylation profile of transformed cells was similar to that of primary cells. Nevertheless, we detected large genomic segments with hypomethylation in the transformed cell residing in gene-poor areas. Furthermore, analysis of 6,000 CpG islands showed that only a small set of promoters was methylated differentially, suggesting that aberrant methylation of CpG island promoters in malignancy might be less frequent than previously hypothesized.

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5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy.

Judith Christman (2002)

5-Azacytidine was first synthesized almost 40 years ago. It was demonstrated to have a wide range of anti-metabolic activities when tested against cultured cancer cells and to be an effective chemotherapeutic agent for acute myelogenous leukemia. However, because of 5-azacytidine's general toxicity, other nucleoside analogs were favored as therapeutics. The finding that 5-azacytidine was incorporated into DNA and that, when present in DNA, it inhibited DNA methylation, led to widespread use of 5-azacytidine and 5-aza-2'-deoxycytidine (Decitabine) to demonstrate the correlation between loss of methylation in specific gene regions and activation of the associated genes. There is now a revived interest in the use of Decitabine as a therapeutic agent for cancers in which epigenetic silencing of critical regulatory genes has occurred. Here, the current status of our understanding of the mechanism(s) by which 5-azacytosine residues in DNA inhibit DNA methylation is reviewed with an emphasis on the interactions of these residues with bacterial and mammalian DNA (cytosine-C5) methyltransferases. The implications of these mechanistic studies for development of less toxic inhibitors of DNA methylation are discussed.

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De novo identification of differentially methylated regions in the human genome

Timothy J. Peters, Michael Buckley, Aaron L Statham … (2015)

Background The identification and characterisation of differentially methylated regions (DMRs) between phenotypes in the human genome is of prime interest in epigenetics. We present a novel method, DMRcate, that fits replicated methylation measurements from the Illumina HM450K BeadChip (or 450K array) spatially across the genome using a Gaussian kernel. DMRcate identifies and ranks the most differentially methylated regions across the genome based on tunable kernel smoothing of the differential methylation (DM) signal. The method is agnostic to both genomic annotation and local change in the direction of the DM signal, removes the bias incurred from irregularly spaced methylation sites, and assigns significance to each DMR called via comparison to a null model. Results We show that, for both simulated and real data, the predictive performance of DMRcate is superior to those of Bumphunter and Probe Lasso, and commensurate with that of comb-p. For the real data, we validate all array-derived DMRs from the candidate methods on a suite of DMRs derived from whole-genome bisulfite sequencing called from the same DNA samples, using two separate phenotype comparisons. Conclusions The agglomeration of genomically localised individual methylation sites into discrete DMRs is currently best served by a combination of DM-signal smoothing and subsequent threshold specification. The findings also suggest the design of the 450K array shows preference for CpG sites that are more likely to be differentially methylated, but its overall coverage does not adequately reflect the depth and complexity of methylation signatures afforded by sequencing. For the convenience of the research community we have created a user-friendly R software package called DMRcate, downloadable from Bioconductor and compatible with existing preprocessing packages, which allows others to apply the same DMR-finding method on 450K array data. Electronic supplementary material The online version of this article (doi:10.1186/1756-8935-8-6) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Guillaume N. Fiches:

ORCID: http://orcid.org/0000-0003-3515-8417

Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Dawei Zhou: Role: ResourcesRole: Writing – review & editing

Weili Kong: Role: ResourcesRole: Writing – review & editing

Ayan Biswas: Role: Writing – review & editing

Elshafa H. Ahmed: Role: ResourcesRole: Writing – review & editing

Robert A. Baiocchi: Role: ResourcesRole: Writing – review & editing

Jian Zhu: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Netty Santoso:

ORCID: http://orcid.org/0000-0003-1175-5831

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Pinghui Feng: Role: Editor

Journal

Journal ID (nlm-ta): PLoS Pathog

Journal ID (iso-abbrev): PLoS Pathog

Journal ID (publisher-id): plos

Journal ID (pmc): plospath

Title: PLoS Pathogens

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Print): 1553-7366

ISSN (Electronic): 1553-7374

Publication date (Electronic): 25 August 2020

Publication date Collection: August 2020

Volume: 16

Issue: 8

Electronic Location Identifier: e1008778

Affiliations

[1 ] Department of Pathology, Ohio State University College of Medicine, Columbus, Ohio, United States of America

[2 ] Gladstone Institute of Virology and Immunology, University of California, San Francisco, California, United States of America

[3 ] Division of Hematology, Department of Internal Medicine, Ohio State University College of Medicine, Columbus, Ohio, United States of America

University of Southern California, UNITED STATES

Author notes

The authors have declared that no competing interests exist.

* E-mail: Jian.Zhu@ 123456osumc.edu (JZ); Netty.Santoso@ 123456osumc.edu (NS)

Author information

Guillaume N. Fiches http://orcid.org/0000-0003-3515-8417

Netty Santoso http://orcid.org/0000-0003-1175-5831

Article

Publisher ID: PPATHOGENS-D-20-00203

DOI: 10.1371/journal.ppat.1008778

PMC ID: 7473590

PubMed ID: 32841292

SO-VID: 36045d62-217d-4c8b-9220-042a763dbdf0

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 31 January 2020

Date accepted : 5 July 2020

Page count

Figures: 8, Tables: 0, Pages: 31

Funding

Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: R01AI150448

Award Recipient : Jian Zhu

Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: R03DE029716

Award Recipient :

ORCID: http://orcid.org/0000-0003-1175-5831

Netty Santoso

Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: R01DE025447

Award Recipient : Jian Zhu

This work was supported by grants to N.S. [R03DE029716] and J.Z. [R01DE025447, R01AI150448] from the National Institute of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLOS Publication Stage vor-update-to-uncorrected-proof

Publication Update 2020-09-04

Data Availability All relevant data are within the manuscript and its Supporting Information files.

Profiling of immune related genes silenced in EBV-positive gastric carcinoma identified novel restriction factors of human gammaherpesviruses

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Most cited references 95

Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells.

5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy.

De novo identification of differentially methylated regions in the human genome

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