N6-methyladenine DNA Modification in Glioblastoma

Qi Xie; Tao P Wu; Ryan C Gimple; Zheng Li; Briana C Prager; Qiulian Wu; Yang Yu; Pengcheng Wang; Yinsheng Wang; David U Gorkin; Cheng Zhang; Alexis V Dowiak; Kaixuan Lin; Chun Zeng; Yinghui Sui; Leo J Y Kim; Tyler E Miller; Li Jiang; Christine Lee-Poturalski; Zhi Huang; Xiaoguang Fang; Kui Zhai; Stephen C Mack; Maike Sander; Shideng Bao; Amber E Kerstetter-Fogle; Andrew E Sloan; Andrew Z Xiao; Jeremy N Rich

doi:10.1016/j.cell.2018.10.006

N⁶-methyladenine DNA Modification in Glioblastoma

Cell. 2018 Nov 15;175(5):1228-1243.e20. doi: 10.1016/j.cell.2018.10.006. Epub 2018 Nov 1.

Authors

Qi Xie¹, Tao P Wu², Ryan C Gimple³, Zheng Li², Briana C Prager⁴, Qiulian Wu¹, Yang Yu⁵, Pengcheng Wang⁵, Yinsheng Wang⁵, David U Gorkin⁶, Cheng Zhang⁶, Alexis V Dowiak⁶, Kaixuan Lin², Chun Zeng⁷, Yinghui Sui⁷, Leo J Y Kim³, Tyler E Miller⁸, Li Jiang¹, Christine Lee-Poturalski⁹, Zhi Huang¹⁰, Xiaoguang Fang¹⁰, Kui Zhai¹⁰, Stephen C Mack¹¹, Maike Sander⁷, Shideng Bao¹⁰, Amber E Kerstetter-Fogle¹², Andrew E Sloan¹², Andrew Z Xiao¹³, Jeremy N Rich¹⁴

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: andrew.xiao@yale.edu.
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: drjeremyrich@gmail.com.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adenine / analogs & derivatives*
Adenine / analysis
Adenine / chemistry
Adult
Aged
AlkB Homolog 1, Histone H2a Dioxygenase / antagonists & inhibitors
AlkB Homolog 1, Histone H2a Dioxygenase / genetics
AlkB Homolog 1, Histone H2a Dioxygenase / metabolism
Animals
Astrocytes / cytology
Astrocytes / metabolism
Brain Neoplasms / metabolism
Brain Neoplasms / mortality
Brain Neoplasms / pathology*
Cell Hypoxia
Child
DNA Methylation*
Epigenomics
Female
Glioblastoma / metabolism
Glioblastoma / mortality
Glioblastoma / pathology*
Heterochromatin / metabolism
Histones / metabolism
Humans
Kaplan-Meier Estimate
Male
Mice
Middle Aged
Neoplastic Stem Cells / cytology
Neoplastic Stem Cells / metabolism
RNA Interference
RNA, Small Interfering / metabolism
Tumor Suppressor Protein p53 / metabolism

Substances

Heterochromatin
Histones
RNA, Small Interfering
Tumor Suppressor Protein p53
ALKBH1 protein, human
AlkB Homolog 1, Histone H2a Dioxygenase
Adenine
6-methyladenine

Abstract

Publication types

MeSH terms

Substances

Grants and funding