PT - JOURNAL ARTICLE AU - Meeri Pekkarinen AU - Kristiina Nordfors AU - Joonas Uusi-Mäkelä AU - Ville Kytölä AU - Minna Rauhala AU - Henna Urhonen AU - Laura Huhtala AU - Sergei Häyrynen AU - Ebrahim Afyounian AU - Olli Yli-Harja AU - Wei Zhang AU - Pauli Helen AU - Olli Lohi AU - Hannu Haapasalo AU - Joonas Haapasalo AU - Matti Nykter AU - Juha Kesseli AU - Kirsi J. Rautajoki TI - Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors AID - 10.1101/2022.03.14.483566 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.03.14.483566 4099 - http://biorxiv.org/content/early/2022/10/01/2022.03.14.483566.short 4100 - http://biorxiv.org/content/early/2022/10/01/2022.03.14.483566.full AB - Atypical teratoid/rhabdoid tumors (AT/RTs) are pediatric brain tumors known for their aggressiveness, exceptionally low mutation rate, and aberrant but still unresolved epigenetic regulation. To evaluate methylation associated regulation in AT/RTs, we compared them to medulloblastomas and choroid plexus tumors by integrating DNA methylation (507 samples), gene expression (120 samples), and public transcription factor (TF) binding data. We showed that elevated DNA methylation masks the binding sites of TFs driving neural development and is associated with reduced transcription for specific neural regulators in AT/RTs. Part of the hypermethylated sites behaved similarly in AT/RTs and pluripotent stem cells, revealing DNA methylation -driven halted cell differentiation. AT/RT-unique DNA hypermethylation was associated with polycomb repressive complex 2 members, like EZH2, and linked to suppressed genes with a role in neural development and tumorigenesis. The obtained results highlight and characterize these DNA methylation programs as drivers of AT/RT malignancy.Competing Interest StatementThe authors have declared no competing interest.