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N 6-methyladenine DNA Modification in Glioblastoma

N 6-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, etc.

Cell. 2018 Nov 15;175(5):1228-1243.e20.

PMID: 30392959

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4246407	Histone H2A human			Price

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