Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors

Meeri Pekkarinen, Kristiina Nordfors, Joonas Uusi-Mäkelä, Ville Kytölä, Anja Hartewig, Laura Huhtala, Minna Rauhala, Henna Urhonen, Sergei Häyrynen, Ebrahim Afyounian, Olli Yli-Harja, Wei Zhang, Pauli Helen, Olli Lohi, Hannu Haapasalo, Joonas Haapasalo, Matti Nykter, Juha Kesseli, Kirsi J. Rautajoki

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Abstract

Atypical teratoid/rhabdoid tumors (AT/RTs) are pediatric brain tumors known for their aggressiveness and aberrant but still unresolved epigenetic regulation. To better understand their malignancy, we investigated how AT/RT-specific DNA hyper-methylation was associated with gene expression and altered transcription factor binding and how it is linked to upstream regulation. Medulloblastomas, choroid plexus tumors, pluripo-tent stem cells, and fetal brain were used as references. A part of the genomic regions, which were hypermethylated in AT/RTs similarly as in pluripotent stem cells and demethylated in the fetal brain, were targeted by neural transcriptional regulators. AT/RT-unique DNA hypermethylation was associated with poly-comb repressive complex 2 and linked to suppressed genes with a role in neural development and tumorigenesis. Activity of the several NEUROG/NEUROD pioneer factors, which are unable to bind to methylated DNA, was compromised via the suppressed expression or DNA hypermethylation of their target sites, which was also experimentally validated for NEUROD1 in medullo-blastomas and AT/RT samples. These results highlight and characterize the role of DNA hypermethylation in AT/RT malignancy and halted neural cell differentiation.

Original languageEnglish
Article numbere202302088
Number of pages18
JournalLife science alliance
Volume7
Issue number6
DOIs
Publication statusPublished - 2024
Publication typeA1 Journal article-refereed

Publication forum classification

  • Publication forum level 1

ASJC Scopus subject areas

  • Ecology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Plant Science
  • Health, Toxicology and Mutagenesis

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