A DNA tumor virus globally reprograms host 3D genome architecture to achieve immortal growth

Chong Wang, Xiang Liu, Jun Liang, Yohei Narita, Weiyue Ding, Difei Li, Luyao Zhang, Hongbo Wang, Merrin Man Long Leong, Isabella Hou, Catherine Gerdt, Chang Jiang, Qian Zhong, Zhonghui Tang, Carmy Forney, Leah Kottyan, Matthew T. Weirauch, Benjamin E. Gewurz, Mu-sheng Zeng, Sizun Jiang (), Mingxiang Teng () and Bo Zhao ()
Additional contact information
Chong Wang: Brigham and Women’s Hospital and Harvard Medical School
Xiang Liu: H. Lee Moffitt Cancer Center and Research Institute
Jun Liang: Brigham and Women’s Hospital and Harvard Medical School
Yohei Narita: Brigham and Women’s Hospital and Harvard Medical School
Weiyue Ding: Brigham and Women’s Hospital and Harvard Medical School
Difei Li: Brigham and Women’s Hospital and Harvard Medical School
Luyao Zhang: Brigham and Women’s Hospital and Harvard Medical School
Hongbo Wang: Brigham and Women’s Hospital and Harvard Medical School
Merrin Man Long Leong: Brigham and Women’s Hospital and Harvard Medical School
Isabella Hou: Brigham and Women’s Hospital and Harvard Medical School
Catherine Gerdt: Brigham and Women’s Hospital and Harvard Medical School
Chang Jiang: Brigham and Women’s Hospital and Harvard Medical School
Qian Zhong: Sun Yat-sen University Cancer Center
Zhonghui Tang: Sun Yat-sen University
Carmy Forney: Cincinnati Children’s Hospital Medical Center
Leah Kottyan: Cincinnati Children’s Hospital Medical Center
Matthew T. Weirauch: Cincinnati Children’s Hospital Medical Center
Benjamin E. Gewurz: Brigham and Women’s Hospital and Harvard Medical School
Mu-sheng Zeng: Sun Yat-sen University Cancer Center
Sizun Jiang: Beth Israel Deaconess Medical Center and Harvard Medical School
Mingxiang Teng: H. Lee Moffitt Cancer Center and Research Institute
Bo Zhao: Brigham and Women’s Hospital and Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Epstein-Barr virus (EBV) immortalization of resting B lymphocytes (RBLs) to lymphoblastoid cell lines (LCLs) models human DNA tumor virus oncogenesis. RBL and LCL chromatin interaction maps are compared to identify the spatial and temporal genome architectural changes during EBV B cell transformation. EBV induces global genome reorganization where contact domains frequently merge or subdivide during transformation. Repressed B compartments in RBLs frequently switch to active A compartments in LCLs. LCLs gain 40% new contact domain boundaries. Newly gained LCL boundaries have strong CTCF binding at their borders while in RBLs, the same sites have much less CTCF binding. Some LCL CTCF sites also have EBV nuclear antigen (EBNA) leader protein EBNALP binding. LCLs have more local interactions than RBLs at LCL dependency factors and super-enhancer targets. RNA Pol II HiChIP and FISH of RBL and LCL further validate the Hi-C results. EBNA3A inactivation globally alters LCL genome interactions. EBNA3A inactivation reduces CTCF and RAD21 DNA binding. EBNA3C inactivation rewires the looping at the CDKN2A/B and AICDA loci. Disruption of a CTCF site at AICDA locus increases AICDA expression. These data suggest that EBV controls lymphocyte growth by globally reorganizing host genome architecture to facilitate the expression of key oncogenes.

Date: 2023
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DOI: 10.1038/s41467-023-37347-6

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