EBNA2 Drives Formation of New Chromosome Binding Sites and Target Genes for B-Cell Master Regulatory Transcription Factors RBP-jκ and EBF1

PLoS Pathogens

Kyoung-Jae Won¹  Fang Lu²  Horng-Shen Chen²  Paul M. Lieberman²  Andrew V. Kossenkov²  Karen DeWispeleare² 

[1] The Institute for Diabetes Obesity and Metabolism, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;The Wistar Institute, Philadelphia, Pennsylvania, United States of America

关键词: Cell binding;    Transcription factors;    B cells;    DNA transcription;    Transcriptional control;    Binding analysis;    Gene expression;    Estradiol;   

DOI  :  10.1371/journal.ppat.1005339

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Epstein-Barr Virus (EBV) transforms resting B-lymphocytes into proliferating lymphoblasts to establish latent infections that can give rise to malignancies. We show here that EBV-encoded transcriptional regulator EBNA2 drives the cooperative and combinatorial genome-wide binding of two master regulators of B-cell fate, namely EBF1 and RBP-jκ. Previous studies suggest that these B-cell factors are statically bound to target gene promoters. In contrast, we found that EBNA2 induces the formation of new binding for both RBP-jκ and EBF1, many of which are in close physical proximity in the cellular and viral genome. These newly induced binding sites co-occupied by EBNA2-EBF1-RBP-jκ correlate strongly with transcriptional activation of linked genes that are important for B-lymphoblast function. Conditional expression or repression of EBNA2 leads to a rapid alteration in RBP-jκ and EBF1 binding. Biochemical and shRNA depletion studies provide evidence for cooperative assembly at co-occupied sites. These findings reveal that EBNA2 facilitate combinatorial interactions to induce new patterns of transcription factor occupancy and gene programming necessary to drive B-lymphoblast growth and survival.

【 授权许可】

CC BY