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N⁶-methyladenine DNA Modification in Glioblastoma.

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.

SUBMITTER: Xie Q

PROVIDER: S-EPMC6433469 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rediscovered as a potential epigenetic mark, N6-methyladenine DNA modification (6mA) was recently reported to be sensitive to environmental stressors in several multicellular eukaryotes. As 6mA distribution and function differ significantly in multicellular and unicellular organisms, whether and how 6mA in unicellular eukaryotes responds to environmental stress remains elusive. Here, we characterized the dynamic changes of 6mA under starvation in the unicellular model organism Tetrahymena thermophila. Single-molecule, real-time (SMRT) sequencing reveals that DNA 6mA levels in starved cells are significantly reduced, especially symmetric 6mA, compared to those in vegetatively growing cells. Despite a global 6mA reduction, the fraction of asymmetric 6mA with a high methylation level was increased, which might be the driving force for stronger nucleosome positioning in starved cells. Starvation affects expression of many metabolism-related genes, the expression level change of which is associated with the amount of 6mA change, thereby linking 6mA with global transcription and starvation adaptation. The reduction of symmetric 6mA and the increase of asymmetric 6mA coincide with the downregulation of AMT1 and upregulation of AMT2 and AMT5, which are supposedly the MT-A70 methyltransferases required for symmetric and asymmetric 6mA, respectively. These results demonstrated that a regulated 6mA response to environmental cues is evolutionarily conserved in eukaryotes. IMPORTANCE Increasing evidence indicated that 6mA could respond to environmental stressors in multicellular eukaryotes. As 6mA distribution and function differ significantly in multicellular and unicellular organisms, whether and how 6mA in unicellular eukaryotes responds to environmental stress remains elusive. In the present work, we characterized the dynamic changes of 6mA under starvation in the unicellular model organism Tetrahymena thermophila. Our results provide insights into how Tetrahymena fine-tunes its 6mA level and composition upon starvation, suggesting that a regulated 6mA response to environmental cues is evolutionarily conserved in eukaryotes.

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N⁶-methyladenine DNA Modification in Glioblastoma.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

N6-methyladenine DNA Modification in Glioblastoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

N⁶-methyladenine DNA Modification in Glioblastoma.