N6-methyladenine DNA Modification in Glioblastoma

• Qi Xie ^[2] ; Tao P. Wu ^[1] ; Ryan C. Gimple ^[2]
  1. [1] Yale University

     Yale University

     Town of New Haven, Estados Unidos

     
  2. [2] University of California, San Diego
• Localización: Cell, ISSN 0092-8674, Vol. 175, Nº. 5, 2018, págs. 1228-1243
• Idioma: inglés
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• Resumen

  • Genetic drivers of cancer can be dysregulated through epigenetic modifications of DNA. Although the critical role of DNA 5-methylcytosine (5mC) in the regulation of transcription is recognized, the functions of other non-canonical DNA modifications remain obscure. Here, we report the identification of novel N6-methyladenine (N6-mA) DNA modifications in human tissues and implicate this epigenetic mark in human disease, specifically the highly malignant brain cancer glioblastoma. Glioblastoma markedly upregulated N6-mA levels, which co-localized with heterochromatic histone modifications, predominantly H3K9me3. N6-mA levels were dynamically regulated by the DNA demethylase ALKBH1, depletion of which led to transcriptional silencing of oncogenic pathways through decreasing chromatin accessibility. Targeting the N6-mA regulator ALKBH1 in patient-derived human glioblastoma models inhibited tumor cell proliferation and extended the survival of tumor-bearing mice, supporting this novel DNA modification as a potential therapeutic target for glioblastoma. Collectively, our results uncover a novel epigenetic node in cancer through the DNA modification N6-mA.