LINE-1 repression in Epstein–Barr virus-associated gastric cancer through viral–host genome interaction

Author:

Zhang Mengyu123,Sun Weikang12,You Xiaoxin12,Xu Dongge12,Wang Lingling12,Yang Jingping12ORCID,Li Erguang1245ORCID,He Susu123ORCID

Affiliation:

1. State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University , Nanjing  210093, China

2. Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University , Nanjing  210093, China

3. Yancheng Medical Research Center, Medical School, Nanjing University , Yancheng  224000, China

4. Institute of Medical Virology, Nanjing Drum Tower Hospital, Medical School, Nanjing University , Nanjing  210093, China

5. Shenzhen Research Institute of Nanjing University , Shenzhen  518000, China

Abstract

AbstractLong INterspersed Element 1 (LINE-1 or L1) acts as a major remodeling force in genome regulation and evolution. Accumulating evidence shows that virus infection impacts L1 expression, potentially impacting host antiviral response and diseases. The underlying regulation mechanism is unclear. Epstein–Barr virus (EBV), a double-stranded DNA virus linked to B-cell and epithelial malignancies, is known to have viral–host genome interaction, resulting in transcriptional rewiring in EBV-associated gastric cancer (EBVaGC). By analyzing publicly available datasets from the Gene Expression Omnibus (GEO), we found that EBVaGC has L1 transcriptional repression compared with EBV-negative gastric cancer (EBVnGC). More specifically, retrotransposition-associated young and full-length L1s (FL-L1s) were among the most repressed L1s. Epigenetic alterations, especially increased H3K9me3, were observed on FL-L1s. H3K9me3 deposition was potentially attributed to increased TASOR expression, a key component of the human silencing hub (HUSH) complex for H3K9 trimethylation. The 4C- and HiC-seq data indicated that the viral DNA interacted in the proximity of the TASOR enhancer, strengthening the loop formation between the TASOR enhancer and its promoter. These results indicated that EBV infection is associated with increased H3K9me3 deposition, leading to L1 repression. This study uncovers a regulation mechanism of L1 expression by chromatin topology remodeling associated with viral–host genome interaction in EBVaGC.

Funder

National Natural Science Foundation of China

Jiangsu Natural Science Foundation

Central Universities Fundamental Research Funds

Science, Technology and Innovation Commission of Shenzhen Municipality

Publisher

Oxford University Press (OUP)

Subject

Genetics

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