N(6)-methyladenine DNA modification in glioblastoma

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Item Type:	Article
Title:	N(6)-methyladenine DNA modification in glioblastoma
Creators Name:	Xie, Q., Wu, T.P., Gimple, R.C., Li, Z., Prager, B.C., Wu, Q., Yu, Y., Wang, P., Wang, Y., Gorkin, D.U., Zhang, C., Dowiak, A.V., Lin, K., Zeng, C., Sui, Y., Kim, L.J.Y., Miller, T.E., Jiang, L., Lee, C.H., Huang, Z., Fang, X.., Zhai, K., Mack, S.C., Sander, M., Bao, S., Kerstetter-Fogle, A.E., Sloan, A.E., Xiao, A.Z. and Rich, J.N.
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 N(6)-methyladenine (N(6)-mA) DNA modifications in human tissues and implicate this epigenetic mark in human disease, specifically the highly malignant brain cancer glioblastoma. Glioblastoma markedly upregulated N(6)-mA levels, which co-localized with heterochromatic histone modifications, predominantly H3K9me3. N(6)-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 N(6)-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 N(6)-mA.
Keywords:	DNA Methylation, N6-Methyladenine, Glioblastoma, Epigenetics, Cancer Stem Cell, Chromatin, Heterochromatin, Neuro-Oncology, Brain Tumor, H3K9me3, Animals, Mice
Source:	Cell
ISSN:	0092-8674
Publisher:	Cell Press
Volume:	175
Number:	5
Page Range:	1228-1243
Date:	15 November 2018
Official Publication:	https://doi.org/10.1016/j.cell.2018.10.006
PubMed:	View item in PubMed

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