N6-methyladenine DNA Modification in Glioblastoma

  • Cell. 2018 Nov 15;175(5):1228-1243.e20. doi: 10.1016/j.cell.2018.10.006.
Qi Xie  1 ,  Tao P Wu  2 ,  Ryan C Gimple  3 ,  Zheng Li  2 ,  Briana C Prager  4 ,  Qiulian Wu  1 ,  Yang Yu  5 ,  Pengcheng Wang  5 ,  Yinsheng Wang  5 ,  David U Gorkin  6 ,  Cheng Zhang  6 ,  Alexis V Dowiak  6 ,  Kaixuan Lin  2 ,  Chun Zeng  7 ,  Yinghui Sui  7 ,  Leo J Y Kim  3 ,  Tyler E Miller  8 ,  Li Jiang  1 ,  Christine H Lee  9 ,  Zhi Huang  10 ,  Xiaoguang Fang  10 ,  Kui Zhai  10 ,  Stephen C Mack  11 ,  Maike Sander  7 ,  Shideng Bao  10 ,  Amber E Kerstetter-Fogle  12 ,  Andrew E Sloan  12 ,  Andrew Z Xiao  13 ,  Jeremy N Rich  14
Affiliations
  • 1. Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
  • 2. Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA.
  • 3. Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH 44120, USA.
  • 4. Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH 44120, USA; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
  • 5. Department of Chemistry, University of California, Riverside, Riverside, CA 92521, USA.
  • 6. Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
  • 7. Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA, 92093, USA.
  • 8. Department of Pathology, Case Western Reserve University, Cleveland, OH 44120, USA.
  • 9. Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44195, USA.
  • 10. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 11. Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.
  • 12. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Neurological Surgery, University Hospitals - Cleveland Medical Center, Cleveland, OH 44106, USA.
  • 13. Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: [email protected].
  • 14. Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92037, USA. Electronic address: [email protected].
PMID: 30392959 DOI: 10.1016/j.cell.2018.10.006
Abstract

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.

Keywords
DNA methylation; H3K9me3; N(6)-methyladenine; brain tumor; cancer stem cell; chromatin; epigenetics; glioblastoma; heterochromatin; neuro-oncology.