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鉴定一种新的 CCCTC 结合因子结合位点，作为 Epstein-Barr 病毒潜伏感染的双重调节子。

Characterization of a new CCCTC-binding factor binding site as a dual regulator of Epstein-Barr virus latent infection.

机构信息

College of Pharmacy, Vessel-Organ Interaction Research Center, Research Institute of Pharmaceutical Science, Kyungpook National University, Daegu, Korea.

Department of Systems Biotechnology, Chung-Ang University, Anseong, Korea.

出版信息

PLoS Pathog. 2023 Jan 25;19(1):e1011078. doi: 10.1371/journal.ppat.1011078. eCollection 2023 Jan.

DOI:10.1371/journal.ppat.1011078
PMID:36696451
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9876287/
Abstract

Distinct viral gene expression characterizes Epstein-Barr virus (EBV) infection in EBV-producing marmoset B-cell (B95-8) and EBV-associated gastric carcinoma (SNU719) cell lines. CCCTC-binding factor (CTCF) is a structural chromatin factor that coordinates chromatin interactions in the EBV genome. Chromatin immunoprecipitation followed by sequencing against CTCF revealed 16 CTCF binding sites in the B95-8 and SNU719 EBV genomes. The biological function of one CTCF binding site (S13 locus) located on the BamHI A right transcript (BART) miRNA promoter was elucidated experimentally. Microscale thermophoresis assay showed that CTCF binds more readily to the stable form than the mutant form of the S13 locus. EBV BART miRNA clusters encode 22 miRNAs, whose roles are implicated in EBV-related cancer pathogenesis. The B95-8 EBV genome lacks a 11.8-kb EcoRI C fragment, whereas the SNU719 EBV genome is full-length. ChIP-PCR assay revealed that CTCF, RNA polymerase II, H3K4me3 histone, and H3K9me3 histone were more enriched at S13 and S16 (167-kb) loci in B95-8 than in the SNU719 EBV genome. 4C-Seq and 3C-PCR assays using B95-8 and SNU719 cells showed that the S13 locus was associated with overall EBV genomic loci including 3-kb and 167-kb region in both EBV genomes. We generated mutations in the S13 locus in bacmids with or without the 11.8-kb BART transcript unit (BART(+/-)). The S13 mutation upregulated BART miRNA expression, weakened EBV latency, and reduced EBV infectivity in the presence of EcoRI C fragment. Another 3C-PCR assay using four types of BART(+/-)·S13(wild-type(Wt)/mutant(Mt)) HEK293-EBV cells revealed that the S13 mutation decreased DNA associations between the 167-kb region and 3-kb in the EBV genome. Based on these results, CTCF bound to the S13 locus along with the 11.8-kb EcoRI C fragment is suggested to form an EBV 3-dimensional DNA loop for coordinated EBV BART miRNA expression and infectivity.

摘要

Epstein-Barr 病毒（EBV）感染在产生 EBV 的绒猴 B 细胞（B95-8）和 EBV 相关胃癌（SNU719）细胞系中表现出独特的病毒基因表达。CCCTC 结合因子（CTCF）是一种结构染色质因子，可协调 EBV 基因组中的染色质相互作用。针对 CTCF 的染色质免疫沉淀和测序显示，B95-8 和 SNU719 EBV 基因组中有 16 个 CTCF 结合位点。实验阐明了位于 BamHI A 右转录物（BART）miRNA 启动子上的一个 CTCF 结合位点（S13 基因座）的生物学功能。微量热泳动分析表明，CTCF 更容易结合稳定形式而不是突变形式的 S13 基因座。EBV BART miRNA 簇编码 22 个 miRNA，其作用与 EBV 相关癌症发病机制有关。B95-8 EBV 基因组缺失 11.8kb EcoRI C 片段，而 SNU719 EBV 基因组是全长的。ChIP-PCR 分析显示，CTCF、RNA 聚合酶 II、H3K4me3 组蛋白和 H3K9me3 组蛋白在 B95-8 中比在 SNU719 EBV 基因组中在 S13 和 S16（167kb）基因座处更为丰富。使用 B95-8 和 SNU719 细胞的 4C-Seq 和 3C-PCR 分析表明，S13 基因座与 EBV 基因组的整体基因组区域相关，包括两个 EBV 基因组中的 3kb 和 167kb 区域。我们在带有或不带有 11.8kb BART 转录单元（BART(+/-)）的 bacmid 中生成 S13 基因座的突变。S13 突变上调了 BART miRNA 的表达，减弱了 EBV 潜伏期，并在存在 EcoRI C 片段的情况下降低了 EBV 的感染力。使用四种类型的 BART(+/-)·S13(wild-type(Wt)/mutant(Mt))HEK293-EBV 细胞进行的另一个 3C-PCR 分析表明，S13 突变减少了 EBV 基因组中 167kb 区域与 3kb 之间的 DNA 关联。基于这些结果，建议与 11.8kb EcoRI C 片段一起结合 S13 基因座的 CTCF 形成 EBV 三维 DNA 环，以协调 EBV BART miRNA 的表达和感染力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/fcc621b4f530/ppat.1011078.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/25d6ae44aaf0/ppat.1011078.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/09dad4d98e76/ppat.1011078.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/a20c4c64478c/ppat.1011078.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/316bcbd557aa/ppat.1011078.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/7774ad7d66bf/ppat.1011078.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/1bac26165f58/ppat.1011078.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/8f823aaff6af/ppat.1011078.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/f1a40aa4ab0d/ppat.1011078.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/a9133cc7ff49/ppat.1011078.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/fcc621b4f530/ppat.1011078.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/25d6ae44aaf0/ppat.1011078.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/09dad4d98e76/ppat.1011078.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/a20c4c64478c/ppat.1011078.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/316bcbd557aa/ppat.1011078.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/7774ad7d66bf/ppat.1011078.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/1bac26165f58/ppat.1011078.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/8f823aaff6af/ppat.1011078.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/f1a40aa4ab0d/ppat.1011078.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/a9133cc7ff49/ppat.1011078.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b28/9876287/fcc621b4f530/ppat.1011078.g010.jpg

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