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Article: Epigenomic landscape study reveals molecular subtypes and EBV-associated regulatory epigenome reprogramming in nasopharyngeal carcinoma

TitleEpigenomic landscape study reveals molecular subtypes and EBV-associated regulatory epigenome reprogramming in nasopharyngeal carcinoma
Authors
KeywordsChromatin accessibility
Epstein-Barr virus
Host-virus interaction
Nasopharyngeal carcinoma
Tumor microenvironment
Whole-genome bisulfite sequencing
Issue Date28-Feb-2023
PublisherElsevier
Citation
EBioMedicine, 2022, v. 86 How to Cite?
Abstract

Background

Epstein-Barr virus (EBV) latent infection is associated with genome-wide epigenomic changes in several malignancies, but its role in epigenetic dysregulation remains unclear in nasopharyngeal carcinoma (NPC).

Methods

To investigate EBV-associated epigenetic dysregulation, we performed a multi-omics study by integrating whole-genome bisulfite sequencing (WGBS), assay for transposase-accessible chromatin using sequencing (ATAC-Seq), whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-Seq) data.

Findings

In addition to the known global DNA hypermethylated subtype, we discovered a novel subtype with global hypomethylation in EBV + NPC. The consistent EBV-specific differentially methylated regions (EBV-DMRs) in the human genome were identified from both subtypes and associated with loss of CTCF binding (P < 2.2e-16). Importantly, CTCF is a master chromatin regulator and CTCF protein was reduced in 45% of NPC cases, especially in those with advanced NPC (Stage IV vs. others: 62% vs. 38%, P = 0.034). This result links EBV with chromatin changes. The ATAC-Seq data suggest regulatory epigenome reprogramming through chromatin accessibility changes in EBV + NPC with altered CTCF binding and the switch of transcription factor binding from differentiation-associated KLF/SP family to the innate and adaptive immunity-related NF-ĸB and IRF families. Detailed chromatin accessibility analysis identified a potential EBV target gene CD74, which mediated EBV-specific cell-cell communications in the tumor microenvironment (TME) and was strongly correlated with T cell exhaustion (r2 = 0.55).

Interpretation

Our study reveals the unexpected epigenetic heterogeneity, providing insights into NPC pathogenesis and highlighting the involvement of host factors in virus-associated epigenetic changes. EBV infection is associated with epigenome reprogramming and may promote immune evasion.


Persistent Identifierhttp://hdl.handle.net/10722/340842
ISSN
2023 Impact Factor: 9.7
2023 SCImago Journal Rankings: 3.193
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorChow, LKY-
dc.contributor.authorChung, DLS-
dc.contributor.authorTao, LH-
dc.contributor.authorChan, KF-
dc.contributor.authorTung, SY-
dc.contributor.authorNgan, RKC-
dc.contributor.authorNg, WT-
dc.contributor.authorLee, AWM-
dc.contributor.authorYau, CC-
dc.contributor.authorKwong, DLW-
dc.contributor.authorLee, VHF-
dc.contributor.authorLam, KO-
dc.contributor.authorLiu, JY-
dc.contributor.authorChen, HL-
dc.contributor.authorDai, W-
dc.contributor.authorLung, ML-
dc.date.accessioned2024-03-11T10:47:42Z-
dc.date.available2024-03-11T10:47:42Z-
dc.date.issued2023-02-28-
dc.identifier.citationEBioMedicine, 2022, v. 86-
dc.identifier.issn2352-3964-
dc.identifier.urihttp://hdl.handle.net/10722/340842-
dc.description.abstract<h3>Background</h3><p>Epstein-Barr virus (EBV) latent infection is associated with genome-wide epigenomic changes in several malignancies, but its role in epigenetic dysregulation remains unclear in nasopharyngeal carcinoma (NPC).</p><h3>Methods</h3><p>To investigate EBV-associated epigenetic dysregulation, we performed a multi-omics study by integrating whole-genome bisulfite sequencing (WGBS), assay for transposase-accessible chromatin using sequencing (ATAC-Seq), whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-Seq) data.</p><h3>Findings</h3><p>In addition to the known global DNA hypermethylated subtype, we discovered a novel subtype with global hypomethylation in EBV + NPC. The consistent EBV-specific differentially methylated regions (EBV-DMRs) in the human genome were identified from both subtypes and associated with loss of CTCF binding (P < 2.2e-16). Importantly, CTCF is a master chromatin regulator and CTCF protein was reduced in 45% of NPC cases, especially in those with advanced NPC (Stage IV vs. others: 62% vs. 38%, P = 0.034). This result links EBV with chromatin changes. The ATAC-Seq data suggest regulatory epigenome reprogramming through chromatin accessibility changes in EBV + NPC with altered CTCF binding and the switch of transcription factor binding from differentiation-associated KLF/SP family to the innate and adaptive immunity-related NF-ĸB and IRF families. Detailed chromatin accessibility analysis identified a potential EBV target gene CD74, which mediated EBV-specific cell-cell communications in the tumor microenvironment (TME) and was strongly correlated with T cell exhaustion (r<sup>2</sup> = 0.55).</p><h3>Interpretation</h3><p>Our study reveals the unexpected epigenetic heterogeneity, providing insights into NPC pathogenesis and highlighting the involvement of host factors in virus-associated epigenetic changes. EBV infection is associated with epigenome reprogramming and may promote immune evasion.</p>-
dc.languageeng-
dc.publisherElsevier-
dc.relation.ispartofEBioMedicine-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectChromatin accessibility-
dc.subjectEpstein-Barr virus-
dc.subjectHost-virus interaction-
dc.subjectNasopharyngeal carcinoma-
dc.subjectTumor microenvironment-
dc.subjectWhole-genome bisulfite sequencing-
dc.titleEpigenomic landscape study reveals molecular subtypes and EBV-associated regulatory epigenome reprogramming in nasopharyngeal carcinoma-
dc.typeArticle-
dc.identifier.doi10.1016/j.ebiom.2022.104357-
dc.identifier.scopuseid_2-s2.0-85141805358-
dc.identifier.volume86-
dc.identifier.eissn2352-3964-
dc.identifier.isiWOS:000904359700001-
dc.identifier.issnl2352-3964-

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