signature=577f630fb15e3c59338fffb9bca5a98c,Next steps in Ewing sarcoma (epi-)genomics

摘要：

and next-generation sequencing (ChIP-Seq) for EWSR1-FLI1 evenly spread peaks appear across the genome with enrichment at GGAA- mSats upstream of EWSR1-FLI1 upregulated genes  [29,30]. However, it became evident that the DNA-binding of EWSR1-FLI1 depends on DNA accessibility and vice versa, that EWSR1-FLI1 strongly impacts the epigenome. Indeed, EWSR1-FLI1 ChIP-Seq peaks close to EWSR1-FLI1 target genes are flanked by his- tone marks typical for the enhancers [18,28,30,31], bound by RNA polymerase II [31] and depleted for repressive marks [28,31]. In contrast, GGAA- mSats in normal human cells feature repressive epigenomic signatures [31].The strong regulatory role of EWSR1-FLI1 in epigenomics is documented by the fact that its expression in HUVEC cells leads to nucleosome depletion, while its knockdown in EwS cells restores nucleosome occupancy [31]. Nucleosome depletion has been reported at the same GGAA- mSats that exhibit histone acetylation in mesen- chymal stem cells (MSCs), which results in more accessible chromatin. Hence, EWSR1-FLI1 likely hijacks the open chromatin structure of MSCs, to eventually induce total nucleosome loss and unfold its oncogenic potential. This lends further support for MSCs representing cells of origin of EwS [32].Deregulation of EWSR1-FLI1 primarily affects the active enhancer mark H3K27ac [18,28], which is enriched at the promoters and enhanc- ers of EWSR1-FLI1 upregulated genes, but depleted at the genes being negatively cor- related with EWSR1-FLI1 expression [28]. H3K27ac peaks, usually, strongly overlap with superenhancers and, consistently, most super- enhancers in EwS show EWSR1-FLI1-binding and H3K27ac modification [28]. Conversely, after downregulation of EWSR1-FLI1 in EwS cells, the chromatin structure resembles that of nontransformed MSCs with major changes in H3K27ac [18].As EWSR1-FLI1 cannot directly modify his- tones, the effect on H3K27ac must be mediated via other proteins [31,33]. In accordance, EWSR1- FLI1 multimers at GGAA-mSats bind to p300 - an acetyltransferase regulating chromatin and enhancer activity - thereby guiding it to regu- latory elements of EWSR1-FLI1 upregulated genes  [18]. At EWSR1-FLI1 repressed genes, one single EWSR1-FLI1 binds to canonical ETS motifs, displacing the normal ETS transcription factors  [18]. In contrast to the wildtype ETS

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