Single cell multiome atlas of pediatric ependymoma

Despite ZFTA-RELA’s potent oncogenic potential, ZFTA-RELA gene fusions are observed exclusively in ependymoma and have never been documented in any other adult or pediatric malignancy. We hypothesized that specific chromatin modules accessible during brain development would render specific cells-of-origin at increased risk of transformation by ZFTA fusion proteins.

To this end we performed integrated single cell ATAC and RNA-seq analysis (referred to as scMultimome) in mouse and human ependymoma tumors driven by the ZFTA-RELA fusion. We demonstrate that specific epi-developmental programs present in radial glia and regulated by Plagl1 are at direct risk of transformation. Oncoprotein engagement of this chromatin module leads to persistent oncogene expression, a failure to halt cellular proliferation, and initiate terminal cellular differentiation.