EBF1 binds to EBNA2 and promotes the assembly of EBNA2 chromatin complexes in B cells
Autor: | Dietmar E. Martin, Sybille Thumann, Cornelia Kuklik-Roos, Laura V. Glaser, Sophie Beer, Ralf Zimmer, Bettina Kempkes, Stefan Krebs, Helmut Blum, Kerstin C. Maier, Marie L. Harth-Hertle, Florian Erhard, Björn Grüning, Simone Rieger, Rolf Backofen |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Herpesvirus 4 Human B Cells viruses Gene Expression Plasma protein binding Regulatory Sequences Nucleic Acid Biochemistry White Blood Cells Cell Signaling immune system diseases Animal Cells hemic and lymphatic diseases Medicine and Health Sciences Promoter Regions Genetic lcsh:QH301-705.5 B-Lymphocytes Chromosome Biology Chromatin binding virus diseases Chromatin medicine.anatomical_structure Epigenetics Cellular Types Genomic Signal Processing Research Article Signal Transduction Protein Binding lcsh:Immunologic diseases. Allergy Cell Binding Cell Physiology Immune Cells Immunology Biology Microbiology Cell Line 03 medical and health sciences Viral Proteins Virology DNA-binding proteins medicine Genetics Humans Gene Regulation Binding site Antibody-Producing Cells Molecular Biology Transcription factor ChIA-PET B cell Blood Cells Biology and Life Sciences Proteins Estrogens Cell Biology biochemical phenomena metabolism and nutrition Molecular biology Hormones ChIP-sequencing Regulatory Proteins 030104 developmental biology lcsh:Biology (General) Epstein-Barr Virus Nuclear Antigens Trans-Activators Parasitology lcsh:RC581-607 Transcription Factors |
Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 13, Iss 10, p e1006664 (2017) PLoS Pathog. 13, e1006664:e1006664 (2017) |
ISSN: | 1553-7374 1553-7366 |
Popis: | Epstein-Barr virus (EBV) infection converts resting human B cells into permanently proliferating lymphoblastoid cell lines (LCLs). The Epstein-Barr virus nuclear antigen 2 (EBNA2) plays a key role in this process. It preferentially binds to B cell enhancers and establishes a specific viral and cellular gene expression program in LCLs. The cellular DNA binding factor CBF1/CSL serves as a sequence specific chromatin anchor for EBNA2. The ubiquitous expression of this highly conserved protein raises the question whether additional cellular factors might determine EBNA2 chromatin binding selectively in B cells. Here we used CBF1 deficient B cells to identify cellular genes up or downregulated by EBNA2 as well as CBF1 independent EBNA2 chromatin binding sites. Apparently, CBF1 independent EBNA2 target genes and chromatin binding sites can be identified but are less frequent than CBF1 dependent EBNA2 functions. CBF1 independent EBNA2 binding sites are highly enriched for EBF1 binding motifs. We show that EBNA2 binds to EBF1 via its N-terminal domain. CBF1 proficient and deficient B cells require EBF1 to bind to CBF1 independent binding sites. Our results identify EBF1 as a co-factor of EBNA2 which conveys B cell specificity to EBNA2. Author summary Epstein-Barr virus (EBV) infection is closely linked to cancer development. At particular risk are immunocompromised individuals like post-transplant patients which can develop B cell lymphomas. In healthy individuals EBV preferentially infects B cells and establishes a latent infection without causing apparent clinical symptoms in most cases. Upon infection, Epstein-Barr virus nuclear antigen 2 (EBNA2) initiates a B cell specific gene expression program that causes activation and proliferation of the infected cells. EBNA2 is a transcription factor well known to use a cellular protein, CBF1/CSL, as a DNA adaptor. CBF1/CSL is a sequence specific DNA binding protein robustly expressed in all tissues. Here we show that EBNA2 can form complexes with early B cell factor 1 (EBF1), a B cell specific DNA binding transcription factor, and EBF1 stabilizes EBNA2 chromatin binding. This EBNA2/EBF1 complex might serve as a novel target to develop future small molecule strategies that act as antivirals in latent B cell infection. |
Databáze: | OpenAIRE |
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