The Epstein-Barr Virus Regulome in Lymphoblastoid Cells

Sizun Jiang; Hufeng Zhou; Jun Liang; Catherine Gerdt; Chong Wang; Liangru Ke; Stefanie C.S. Schmidt; Yohei Narita; Yijie Ma; Shuangqi Wang; Tyler Colson; Benjamin Gewurz; Guoliang Li; Elliott Kieff; Bo Zhao

doi:10.1016/j.chom.2017.09.001

The Epstein-Barr Virus Regulome in Lymphoblastoid Cells

Sizun Jiang, Hufeng Zhou, Jun Liang, Catherine Gerdt, Chong Wang, Liangru Ke, Stefanie C.S. Schmidt, Yohei Narita, Yijie Ma, Shuangqi Wang, Tyler Colson, Benjamin Gewurz, Guoliang Li, Elliott Kieff, Bo Zhao

Research output: Contribution to journal › Article › peer-review

79 Scopus citations

Abstract

Epstein-Barr virus (EBV) transforms B cells to continuously proliferating lymphoblastoid cell lines (LCLs), which represent an experimental model for EBV-associated cancers. EBV nuclear antigens (EBNAs) and LMP1 are EBV transcriptional regulators that are essential for LCL establishment, proliferation, and survival. Starting with the 3D genome organization map of LCL, we constructed a comprehensive EBV regulome encompassing 1,992 viral/cellular genes and enhancers. Approximately 30% of genes essential for LCL growth were linked to EBV enhancers. Deleting EBNA2 sites significantly reduced their target gene expression. Additional EBV super-enhancer (ESE) targets included MCL1, IRF4, and EBF. MYC ESE looping to the transcriptional stat site of MYC was dependent on EBNAs. Deleting MYC ESEs greatly reduced MYC expression and LCL growth. EBNA3A/3C altered CDKN2A/B spatial organization to suppress senescence. EZH2 inhibition decreased the looping at the CDKN2A/B loci and reduced LCL growth. This study provides a comprehensive view of the spatial organization of chromatin during EBV-driven cellular transformation. Jiang et al. examine the 3D chromatin landscape of Epstein-Barr virus (EBV)-transformed B cells to build the EBV regulome. Viral EBNA and LMP proteins regulate host gene expression through long-range enhancer-promoter looping to activate key oncogenes and inactivate tumor suppressor genes in lymphoblastoid cells.

Original language	English (US)
Pages (from-to)	561-573.e4
Journal	Cell Host and Microbe
Volume	22
Issue number	4
DOIs	https://doi.org/10.1016/j.chom.2017.09.001
State	Published - Oct 11 2017
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

CDKN2A/B
ChIA-PET
EBV regulome
EBV super-enhancers
Epstein-Barr virus
MYC

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chom.2017.09.001

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title = "The Epstein-Barr Virus Regulome in Lymphoblastoid Cells",

abstract = "Epstein-Barr virus (EBV) transforms B cells to continuously proliferating lymphoblastoid cell lines (LCLs), which represent an experimental model for EBV-associated cancers. EBV nuclear antigens (EBNAs) and LMP1 are EBV transcriptional regulators that are essential for LCL establishment, proliferation, and survival. Starting with the 3D genome organization map of LCL, we constructed a comprehensive EBV regulome encompassing 1,992 viral/cellular genes and enhancers. Approximately 30% of genes essential for LCL growth were linked to EBV enhancers. Deleting EBNA2 sites significantly reduced their target gene expression. Additional EBV super-enhancer (ESE) targets included MCL1, IRF4, and EBF. MYC ESE looping to the transcriptional stat site of MYC was dependent on EBNAs. Deleting MYC ESEs greatly reduced MYC expression and LCL growth. EBNA3A/3C altered CDKN2A/B spatial organization to suppress senescence. EZH2 inhibition decreased the looping at the CDKN2A/B loci and reduced LCL growth. This study provides a comprehensive view of the spatial organization of chromatin during EBV-driven cellular transformation. Jiang et al. examine the 3D chromatin landscape of Epstein-Barr virus (EBV)-transformed B cells to build the EBV regulome. Viral EBNA and LMP proteins regulate host gene expression through long-range enhancer-promoter looping to activate key oncogenes and inactivate tumor suppressor genes in lymphoblastoid cells.",

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AU - Jiang, Sizun

AU - Zhou, Hufeng

AU - Liang, Jun

AU - Gerdt, Catherine

AU - Wang, Chong

AU - Ke, Liangru

AU - Schmidt, Stefanie C.S.

AU - Narita, Yohei

AU - Ma, Yijie

AU - Wang, Shuangqi

AU - Colson, Tyler

AU - Gewurz, Benjamin

AU - Li, Guoliang

AU - Kieff, Elliott

AU - Zhao, Bo

PY - 2017/10/11

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N2 - Epstein-Barr virus (EBV) transforms B cells to continuously proliferating lymphoblastoid cell lines (LCLs), which represent an experimental model for EBV-associated cancers. EBV nuclear antigens (EBNAs) and LMP1 are EBV transcriptional regulators that are essential for LCL establishment, proliferation, and survival. Starting with the 3D genome organization map of LCL, we constructed a comprehensive EBV regulome encompassing 1,992 viral/cellular genes and enhancers. Approximately 30% of genes essential for LCL growth were linked to EBV enhancers. Deleting EBNA2 sites significantly reduced their target gene expression. Additional EBV super-enhancer (ESE) targets included MCL1, IRF4, and EBF. MYC ESE looping to the transcriptional stat site of MYC was dependent on EBNAs. Deleting MYC ESEs greatly reduced MYC expression and LCL growth. EBNA3A/3C altered CDKN2A/B spatial organization to suppress senescence. EZH2 inhibition decreased the looping at the CDKN2A/B loci and reduced LCL growth. This study provides a comprehensive view of the spatial organization of chromatin during EBV-driven cellular transformation. Jiang et al. examine the 3D chromatin landscape of Epstein-Barr virus (EBV)-transformed B cells to build the EBV regulome. Viral EBNA and LMP proteins regulate host gene expression through long-range enhancer-promoter looping to activate key oncogenes and inactivate tumor suppressor genes in lymphoblastoid cells.

AB - Epstein-Barr virus (EBV) transforms B cells to continuously proliferating lymphoblastoid cell lines (LCLs), which represent an experimental model for EBV-associated cancers. EBV nuclear antigens (EBNAs) and LMP1 are EBV transcriptional regulators that are essential for LCL establishment, proliferation, and survival. Starting with the 3D genome organization map of LCL, we constructed a comprehensive EBV regulome encompassing 1,992 viral/cellular genes and enhancers. Approximately 30% of genes essential for LCL growth were linked to EBV enhancers. Deleting EBNA2 sites significantly reduced their target gene expression. Additional EBV super-enhancer (ESE) targets included MCL1, IRF4, and EBF. MYC ESE looping to the transcriptional stat site of MYC was dependent on EBNAs. Deleting MYC ESEs greatly reduced MYC expression and LCL growth. EBNA3A/3C altered CDKN2A/B spatial organization to suppress senescence. EZH2 inhibition decreased the looping at the CDKN2A/B loci and reduced LCL growth. This study provides a comprehensive view of the spatial organization of chromatin during EBV-driven cellular transformation. Jiang et al. examine the 3D chromatin landscape of Epstein-Barr virus (EBV)-transformed B cells to build the EBV regulome. Viral EBNA and LMP proteins regulate host gene expression through long-range enhancer-promoter looping to activate key oncogenes and inactivate tumor suppressor genes in lymphoblastoid cells.

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KW - EBV regulome

KW - EBV super-enhancers

KW - Epstein-Barr virus

KW - MYC

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VL - 22

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JO - Cell Host and Microbe

JF - Cell Host and Microbe

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ER -

The Epstein-Barr Virus Regulome in Lymphoblastoid Cells

Abstract

Bibliographical note

Keywords

UN SDGs

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