By genetic inhibition of CTCF sites in ZFTA ependymoma lines, we provide evidence that insulator dysfunction is a potential oncogenic mechanism associated with transcriptional activation of the PFA tumor-dependency genes ARL4C and NELFB. Overall, our study has identified several group-specific tumor dependencies in ependymomas, opening avenues for potential therapeutic interventions that are urgently needed for this disease, especially for ZFTA and PFA ependymoma patients. The gene discussed is CTCF; the disease is ependymoma.