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| Status |
Public on Mar 03, 2016 |
| Title |
RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
In B cells infected by the cancer-associated Epstein-Barr virus (EBV), RUNX3 and RUNX1 transcription is manipulated to control cell growth. The EBV-encoded EBNA2 transcription factor (TF) activates RUNX3 transcription leading to RUNX3-mediated repression of the RUNX1 promoter and the relief of RUNX1-directed growth repression. We show that EBNA2 activates RUNX3 through a specific element within a -97 kb super-enhancer in a manner dependent on the expression of the Notch DNA-binding partner RBP-J. We also reveal that the EBV TFs EBNA3B and EBNA3C contribute to RUNX3 activation in EBV-infected cells by targeting the same element. Uncovering a counter-regulatory feed-forward step, we demonstrate EBNA2 activation of a RUNX1 super-enhancer (-139 to -250 kb) that results in low-level RUNX1 expression in cells refractory to RUNX1-mediated growth inhibition. EBNA2 activation of the RUNX1 super-enhancer is also dependent on RBP-J. Consistent with the context-dependent roles of EBNA3B and EBNA3C as activators or repressors, we find that these proteins negatively regulate the RUNX1 super-enhancer, curbing EBNA2 activation. Taken together our results reveal cell-type specific exploitation of RUNX gene super-enhancers by multiple EBV TFs via the Notch pathway to fine tune RUNX3 and RUNX1 expression and manipulate B-cell growth.
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| Overall design |
Examination of EBNA2 protein binding using a monoclonal antibody (PE2) in single ChIP-seq experiments carried out in the human GM12878 EBV transformed lymphoblastoid cell line.
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| Contributor(s) |
Gunnell A, Webb HM, Wood CD, McClellan MJ, Wichaidit B, Kempkes B, Jenner RG, Osborne C, Farrell PJ, West MJ |
| Citation(s) |
26883634 |
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| Submission date |
Jan 14, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Richard Jenner |
| E-mail(s) |
r.jenner@ucl.ac.uk
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| Organization name |
UCL Cancer Institute
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| Department |
Cancer Biology
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| Lab |
Regulatory Genomics
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| Street address |
72 Huntley Street
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| City |
London |
| ZIP/Postal code |
WC1E 6BT |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL10999 |
Illumina Genome Analyzer IIx (Homo sapiens) |
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| Samples (3) |
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| Relations |
| BioProject |
PRJNA308834 |
| SRA |
SRP068462 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE76869_RAW.tar |
150.0 Kb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Processed data provided as supplementary file |
| Raw data are available in SRA |
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