Journal Article

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

Wang, Hongbo, Liu, Xiang, Jiang, Sizun, Weirauch, Matthew T., Narita, Yohei, Ding, Weiyue, Teng, Mingxiang, Forney, Carmy, Liang, Jun, Jiang, Chang, Zeng, Mu-sheng, Tang, Zhonghui, Kottyan, Leah, Zhao, Bo, Wang, Chong, Gerdt, Catherine, Hou, Isabella, Zhong, Qian, Zhang, Luyao, Gewurz, Benjamin E., Li, Difei, Leong, Merrin Man Long

2023

Overview

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. The dynamic and temporal changes of host genome architecture during Epstein-Barr virus (EBV) transformation are not well known. Here the authors transform human primary B lymphocyte into lymphoblastoid cell lines (LCLs) with EBV and show that the host 3D genome is rewired to facilitate expression of key oncogenes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/15 / 49 / 49/23 / 631/208/176 / 692/420/2489/68 / Antigens / B-Lymphocytes - metabolism / Binding / Boundaries / Cell culture / Cell Line / Chromatin / Compartments / Deactivation / Deoxyribonucleic acid / DNA / DNA tumor viruses / DNA viruses / DNA-directed RNA polymerase / Domains / EBNA-3C protein / Epstein-Barr virus / Epstein-Barr Virus Infections / Epstein-Barr Virus Nuclear Antigens - metabolism / Gene expression / Gene mapping / Genomes / Herpesvirus 4, Human - physiology / Humanities and Social Sciences / Humans / Immortalization / Inactivation / Loci / Lymphoblastoid cell lines / Lymphocytes / Lymphocytes B / multidisciplinary / Protein sorting signals / Science / Science (multidisciplinary) / Transformations (mathematics) / Tumorigenesis / Tumors / Viruses