Cross-species chromatin interactions drive transcriptional rewiring in Epstein-Barr virus-positive gastric adenocarcinoma
Cross-species chromatin interactions drive transcriptional rewiring in Epstein-Barr virus-positive gastric adenocarcinoma
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DOI：
10.1038/s41588-020-0665-7
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发表时间：
2020-07-27
期刊：
影响因子：
30.8
通讯作者：
Kaneda, Atsushi
中科院分区：
文献类型：
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作者：
Okabe, Atsushi;Huang, Kie Kyon;Kaneda, Atsushi
EB病毒（EBV）与几种人类恶性肿瘤有关，包括8-10%的胃癌（GC）。对GC系、原发组织和正常胃样品的3D染色质拓扑结构的全基因组分析揭示了EBV阳性GC特异性的染色质结构域，表现出异染色质至常染色质的转变和与非整合的EBV附加体的长距离人病毒相互作用。体外EBV感染足以重塑染色质拓扑结构和EBV相互作用宿主基因组位点的功能，将H3 K9 me 3（+）异染色质转化为H3 K4 me 1（+）/H3 K27 ac（+）二价，并释放潜在的增强子以接合和激活附近的GC相关基因（例如TGFBR 2和MZT 1）。因此，EBV阳性GC的高阶表观基因型意味着一种新的致癌模式，即非整合型病毒基因组可以直接改变宿主的表观遗传景观胃癌中3D染色质拓扑结构的全基因组分析表明，EB病毒感染可能通过人-病毒染色质相互作用诱导EBV阳性肿瘤的表观遗传重新布线，这种现象被称为“增强子侵染”。
Epstein-Barr virus (EBV) is associated with several human malignancies including 8-10% of gastric cancers (GCs). Genome-wide analysis of 3D chromatin topologies across GC lines, primary tissue and normal gastric samples revealed chromatin domains specific to EBV-positive GC, exhibiting heterochromatin-to-euchromatin transitions and long-range human-viral interactions with non-integrated EBV episomes. EBV infection in vitro suffices to remodel chromatin topology and function at EBV-interacting host genomic loci, converting H3K9me3(+)heterochromatin to H3K4me1(+)/H3K27ac(+)bivalency and unleashing latent enhancers to engage and activate nearby GC-related genes (for exampleTGFBR2andMZT1). Higher-order epigenotypes of EBV-positive GC thus signify a novel oncogenic paradigm whereby non-integrative viral genomes can directly alter host epigenetic landscapes ('enhancer infestation'), facilitating proto-oncogene activation and tumorigenesis.Genome-wide analysis of 3D chromatin topologies across gastric cancers suggests that Epstein-Barr virus infection may induce the epigenetic rewiring of EBV-positive tumors through human-viral chromatin interactions, a phenomenon termed 'enhancer infestation'.