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Epigenome mapping reveals distinct modes of gene regulation and widespread
enhancer reprogramming by the oncogenic fusion protein EWS-FLI1
#MMPMID25704812
Tomazou EM
; Sheffield NC
; Schmidl C
; Schuster M
; Schönegger A
; Datlinger P
; Kubicek S
; Bock C
; Kovar H
Cell Rep
2015[Feb]; 10
(7
): 1082-95
PMID25704812
show ga
Transcription factor fusion proteins can transform cells by inducing global
changes of the transcriptome, often creating a state of oncogene addiction. Here,
we investigate the role of epigenetic mechanisms in this process, focusing on
Ewing sarcoma cells that are dependent on the EWS-FLI1 fusion protein. We
established reference epigenome maps comprising DNA methylation, seven histone
marks, open chromatin states, and RNA levels, and we analyzed the epigenome
dynamics upon downregulation of the driving oncogene. Reduced EWS-FLI1 expression
led to widespread epigenetic changes in promoters, enhancers, and
super-enhancers, and we identified histone H3K27 acetylation as the most strongly
affected mark. Clustering of epigenetic promoter signatures defined classes of
EWS-FLI1-regulated genes that responded differently to low-dose treatment with
histone deacetylase inhibitors. Furthermore, we observed strong and opposing
enrichment patterns for E2F and AP-1 among EWS-FLI1-correlated and anticorrelated
genes. Our data describe extensive genome-wide rewiring of epigenetic cell states
driven by an oncogenic fusion protein.
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