Abstract
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 Statement
The authors have declared no competing interest.
Footnotes
Shifted the focus to atypical teratoid/rhabdoid tumors (AT/RTs). Investigated the contribution of different AT/RT subgroups on our results and found that the detected methylation patterns were largely shared between AT/RT subgroups. Unified the criteria for differential DNA methylation used for TF-enrichment and gene expression correlation analysis. Figure 1 updated. Figure 2 revisited. Figure 3 updated. Figure 4 updated. Manuscript text and title updated to reflect these changes. The corresponding author changed her name, which was updated.
