RNA-seq of EBVwt or EBVmutant infected human primary B cells on day 1, 2, 3, and 4 post-infection
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 1500
ORGANISM(S): Homo sapiens
SUBMITTER: Sophie Beer
PROVIDER: E-MTAB-11350 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Gene expression programs depend on sequence-specific DNA binding transcription factors, but the mechanisms that control the selective binding of these factors in a chromosomal and genomic context remain enigmatic. Here, we show that two master regulators of B-cell fate, namely EBF1 and RBP-jk, show variable genome-wide chromosome distribution in two related B-lymphocyte lines carrying different forms of Epstein-Barr Virus (EBV) latency. The latency-type specific EBV-encoded EBNA2 colocalized with RBP-jk and EBF1 at induced binding sites. Colocalization of EBF1, RBP-jk, and EBNA2 correlated with transcriptional activation. Conditional expression or repression of EBNA2 lead to a rapid alteration in RBP-jk and EBF1 binding. Biochemical and shRNA depletion studies provide evidence for cooperative assembly at co-occupied sites. These findings reveal that non-DNA binding cofactors can facilitate combinatorial interactions to induce new patterns of transcription factor occupancy and gene programming Examination of EBNA2/EBF1/EBP-jk binding in MutuI and LCL cell lines
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Project description:Epstein-Barr virus (EBV) infection converts resting human B cells into permanently growing lymphoblastoid cell lines (LCLs). The viral Epstein-Barr virus nuclear antigen 2 (EBNA2) plays 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. Both, CBF1 independent EBNA2 target genes and chromatin binding sites 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 in CBF1 proficient and deficient B cells and requires 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. In order to test, if EBNA2 can exert any functions in the absence of its DNA adaptor CBF1, a microarray based genome wide screen for EBNA2 target genes in DG75 B cells that are either proficient (wt) or deficient (ko) for CBF1 was performed. CBF1 deficient DG75 cells (SM224.9) cells had been generated by gene targeting using homologous recombination in the somatic B cell line DG75. Both cell lines, the CBF1 proficient DG75 parental cell line and the CBF1 deficient somatic knock-out cell line constitutively express an estrogen receptor (ER) hormone binding domain EBNA2 fusion protein (ER/EBNA2). ER/EBNA2 is retained in the cytoplasm of the cell but is rapidly activated and translocated to the nucleus in response to estrogen. For expression profiling, DG75, DG75 CBF1 ko (SM224.9), DG75 ER/EBNA2 CBF1 wt (SM295 D6) and DG75 ER/EBNA2 CBF1 ko (SM296 D3) cells were cultured in estrogen supplemented media for 24 h, total cellular RNAs were harvested and processed for the hybridization of gene arrays. The cellular system used for this study has been published: Maier S, Santak M, Mantik A, Grabusic K, Kremmer E, Hammerschmidt W, et al. A somatic knockout of CBF1 in a human B-cell line reveals that induction of CD21 and CCR7 by EBNA-2 is strictly CBF1 dependent and that downregulation of immunoglobulin M is partially CBF1 independent. Journal of Virology. 2005 Jul;79(14):8784-92. PubMed PMID: 15994772.
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