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The presence of<jats:italic> RELA<\/jats:italic> as the fusion partner indicates a close association of aberrant NF-\u03baB activity with tumorigenesis. However, the oncogenic role of the<jats:italic> C11orf95<\/jats:italic> has not been determined. Here, we performed ChIP-seq analyses to explore genomic regions bound by RELA<jats:sup>FUS<\/jats:sup> and H3K27ac proteins in human 293\u00a0T and mouse ependymoma cells. We then utilized published RNA-Seq data from human and mouse RELA<jats:sup>FUS<\/jats:sup> tumors and identified target genes that were directly regulated by<jats:italic> RELA<\/jats:italic><jats:sup><jats:italic>FUS<\/jats:italic><\/jats:sup> in these tumors. Subsequent transcription factor motif analyses of RELA<jats:sup>FUS<\/jats:sup> target genes detected a unique GC-rich motif recognized by the C11orf95 moiety, that is present in approximately half of RELA<jats:sup>FUS<\/jats:sup> target genes. Luciferase assays confirmed that a promoter carrying this motif is sufficient to drive RELA<jats:sup>FUS<\/jats:sup>-dependent gene expression. Further, the RELA<jats:sup>FUS<\/jats:sup> target genes were found to be overlapped with Rela target genes primarily via non-canonical NF-\u03baB binding sites. Using a series of truncation and substitution mutants of<jats:italic> RELA<\/jats:italic><jats:sup><jats:italic>FUS<\/jats:italic><\/jats:sup>, we also show that the activation domain in the RELA<jats:sup>FUS<\/jats:sup> moiety is necessary for the regulation of gene expression of these RELA<jats:sup>FUS<\/jats:sup> target genes. Lastly, we performed an anti-cancer drug screening with mouse ependymoma cells and identified potential anti-ependymoma drugs that are related to the oncogenic mechanism of<jats:italic> RELA<\/jats:italic><jats:sup><jats:italic>FUS<\/jats:italic><\/jats:sup>. These findings suggested that <jats:italic>RELA<\/jats:italic><jats:sup><jats:italic>FUS<\/jats:italic><\/jats:sup> might induce ependymoma formation through oncogenic pathways orchestrated by both C11orf95 and RELA target genes. Thus, our study unveils a complex gene function of<jats:italic> RELA<\/jats:italic><jats:sup><jats:italic>FUS<\/jats:italic><\/jats:sup> as an oncogenic transcription factor in <jats:italic>RELA<\/jats:italic><jats:sup><jats:italic>FUS<\/jats:italic><\/jats:sup> positive ependymomas.<\/jats:p>","DOI":"10.1186\/s40478-021-01135-4","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T13:04:21Z","timestamp":1615208661000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["C11orf95-RELA fusion drives aberrant gene expression through the unique epigenetic regulation for ependymoma formation"],"prefix":"10.1186","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8424-1562","authenticated-orcid":false,"given":"Tatsuya","family":"Ozawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4558-9800","authenticated-orcid":false,"given":"Syuzo","family":"Kaneko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Szulzewsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mutsumi","family":"Takadera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitaka","family":"Narita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Kondo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric C.","family":"Holland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuji","family":"Hamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Ichimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,8]]},"reference":[{"key":"1135_CR1","doi-asserted-by":"publisher","first-page":"W202","DOI":"10.1093\/nar\/gkp335","volume":"37","author":"TL Bailey","year":"2009","unstructured":"Bailey TL, Boden M, Buske FA, Frith M, Grant CE, Clementi L, Ren J, Li WW, Noble WS (2009) MEME SUITE: tools for motif discovery and searching. 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