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
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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