Phase separation of Epstein-Barr virus EBNA2 protein reorganizes chromatin topology for epigenetic regulation

Yiting Yang,Yongchang Zhu,Bingtao Hao,Xidong Ye,Litao Qin,Delong Feng,Shixiu Liao,Wei Xue,Yan Zhang,Ranran Dai,Zhaoqiang Li,Bo Lei,Xin Wang

doi:10.1038/s42003-021-02501-7

Abstract

Epstein-Barr virus nuclear antigen 2 (EBNA2) is a transactivator of viral and cellular gene expression, which plays a critical role in the Epstein-Barr virus-associated diseases. It was reported that EBNA2 regulates gene expression by reorganizing chromatin and manipulating epigenetics. Recent studies showed that liquid-liquid phase separation plays an essential role in epigenetic and transcriptional regulation. Here we show that EBNA2 reorganized chromatin topology to form accessible chromatin domains (ACDs) of the host genome by phase separation. The N-terminal region of EBNA2, which is necessary for phase separation, is sufficient to induce ACDs. The C-terminal domain of EBNA2 promotes the acetylation of accessible chromatin regions by recruiting histone acetylase p300 to ACDs. According to these observations, we proposed a model of EBNA2 reorganizing chromatin topology for its acetylation through phase separation to explain the mechanism of EBNA2 hijacking the host genome by controlling its epigenetics.

Highlights

Epstein-Barr virus nuclear antigen 2 (EBNA2) is a transactivator of viral and cellular gene expression, which plays a critical role in the Epstein-Barr virus-associated diseases
We analyzed the key domain of EBNA2 for phase separation and its role in chromatin topology using an assay of transposase-accessible chromatin with visualization (ATAC-see)
It was reported that activation domains of transcription factors form phase-separation condensates with the Mediator coactivator to activate genes[46]

Summary

Introduction

Epstein-Barr virus nuclear antigen 2 (EBNA2) is a transactivator of viral and cellular gene expression, which plays a critical role in the Epstein-Barr virus-associated diseases. Recent studies showed that liquid-liquid phase separation plays an essential role in epigenetic and transcriptional regulation. We show that EBNA2 reorganized chromatin topology to form accessible chromatin domains (ACDs) of the host genome by phase separation. EBNA2 is the main transactivator of the virus nuclear proteins and regulates latent viral transcription and genes of host cells[3]. A recent study reported that EBNA2 has an intrinsic feature of phase separation and form nuclear puncta with a property of liquid-like condensates[25]. The C-terminal transactivation domain (C-TAD) of EBNA2 recruits histone acetyltransferase p300 into ACDs to acetylate histone H3K27 in the accessible chromatin regions.

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Results

Conclusion