DNA N6-methyladenine is dynamically regulated in the mouse brain following environmental stress

Yao, Bing; Cheng, Ying; Wang, Zhiqin; Li, Yujing; Chen, Li; Huang, Luoxiu; Zhang, Wenxin; Chen, Dahua; Wu, Hao; Tang, Beisha; Jin, Peng

doi:10.1038/s41467-017-01195-y

Cited by 182 publications

(151 citation statements)

References 56 publications

Supporting

Mentioning

137

Contrasting

Order By: Relevance

“…One of the top ranking motifs (GGAAT) closely resembles human major satellite repeats that are enriched at constutitive heterochromatic regions (Figure S2C). Consistent with findings that DNA N 6 -mA functions as a repressive mark in murine ESCs and brains (Wu et al, 2016; Yao et al, 2017), these data suggest that N 6 -mA-mediated repression of neurodevelopmental pathways may serve a role in heterochromatin formation that contributes to glioblastoma tumorigenesis.…”

Section: Resultssupporting

confidence: 87%

See 1 more Smart Citation

N-methyladenine DNA Modification in Glioblastoma

Xie

Gimple

et al. 2018

Cell

243

254

View full text Add to dashboard Cite

SUMMARY Genetic drivers of cancer can be dysregulated through epigenetic modifications of DNA. While the critical role of DNA 5-methylcytosine (5mC) in the regulation of transcription is recognized, the functions of other non-canonical DNA modifications remain obsure. Here, we report the identification of novel N(6)-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 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.

show abstract

Section: Resultssupporting

confidence: 87%

“…We and others reported that DNA undergoes rare N 6 -mA modification in low and high eukaryotes (Fu et al, 2015; Greer et al, 2015; Wu et al, 2016; Xiao et al, 2018; Yao et al, 2017; Zhang et al, 2015). However, the biological function of N 6 -mA in human cancers remains unclear.…”

Section: Discussionmentioning

confidence: 92%

N-methyladenine DNA Modification in Glioblastoma

Xie

Gimple

et al. 2018

Cell

243

254

View full text Add to dashboard Cite

show abstract

“…Similarly, there could be epigenetic changes in the promoter of DNMT1 that could lead to altered DNMT1 mRNA and activity. In addition, a recent study reported that global m6A in the brain is increased upon stress (87). This finding suggests that m6A, although low in vertebrates (88), could play an important role in the development of neuropsychiatric disorders (87).…”

Section: Discussionmentioning

confidence: 96%

“…In addition, a recent study reported that global m6A in the brain is increased upon stress (87). This finding suggests that m6A, although low in vertebrates (88), could play an important role in the development of neuropsychiatric disorders (87). On the basis of our finding that 5mC is decreased in the H67D brain, it is interesting to further investigate whether H67D mutation/iron overload alters noncanonical methylation of DNA, such as m6A and m4C, and if changes in these epigenetic modifications contribute to altered GABAergic neurochemistry.…”

Section: Discussionmentioning

confidence: 99%

Brain iron loading impairs DNA methylation and alters GABAergic function in mice

Trivedi

Zhang

et al. 2018

FASEB j.

View full text Add to dashboard Cite

Iron deficiency is closely associated with altered GABA metabolism and affective behavior. While mutation in the hemochromatosis (HFE) gene disrupts iron homeostasis and promotes oxidative stress that increases the risk of neurodegeneration, it is largely unknown whether HFE mutation modifies GABAergic homeostasis and emotional behavior. The goal of our study was to investigate the impact of HFE on GABAergic neurochemistry and redox–epigenetic regulation in the brain using H67D HFE‐mutant mice that recapitulates the H63D‐HFE mutation in humans. H67D mice displayed elevated redox‐active iron levels in the brain by 32% compared to age‐matched wild‐type mice. Moreover, the H67D brain had increased isoprostane and decreased glutathione, indicating elevated oxidative stress. Additionally, the H67D brain had decreased global methylation and attenuated DNA methyltransferase (DNMT) activity. Direct addition of iron to purified DNMT in vitro decreased enzyme activity in a concentration‐dependent manner. Last, H67D mice exhibited decreased anxiety‐like behavior, which was associated with increased expression of the GABAA receptor α2 subunits by 93%, and these changes were also observed in H67D mice fed a low‐iron diet. Taken together, our results suggest a putative role of HFE in regulating labile iron status in the brain, and mutation in H67D perturbs redox‐methylation status, contributing to GABAergic dysfunction.—Ye, Q., Trivedi, M., Zhang, Y., Böhlke, M., Alsulimani, H., Chang, J., Maher, T., Deth, R., Kim, J. Brain iron loading impairs DNA methylation and alters GABAergic function in mice. FASEB J. 33, 2460–2471 (2019). http://www.fasebj.org

show abstract

“…1a). Non-cytosine modifications, though rarer still, are also beginning to be investigated (Yao et al 2017).…”

Section: Nature and Regulation Of Dna Modificationsmentioning

confidence: 99%

Analysis of DNA modifications in aging research

et al. 2018

View full text Add to dashboard Cite

As geroscience research extends into the role of epigenetics in aging and age-related disease, researchers are being confronted with unfamiliar molecular techniques and data analysis methods that can be difficult to integrate into their work. In this review, we focus on the analysis of DNA modifications, namely cytosine methylation and hydroxymethylation, through nextgeneration sequencing methods. While older techniques for modification analysis performed relative quantitation across regions of the genome or examined average genome levels, these analyses lack the desired specificity, rigor, and genomic coverage to firmly establish the nature of genomic methylation patterns and their response to aging. With recent methodological advances, such as whole genome bisulfite sequencing (WGBS), bisulfite oligonucleotide capture sequencing (BOCS), and bisulfite amplicon sequencing (BSAS), cytosine modifications can now be readily analyzed with base-specific, absolute quantitation at both cytosine-guanine dinucleotide (CG) and non-CG sites throughout the genome or within specific regions of interest by next-generation sequencing. Additional advances, such as oxidative bisulfite conversion to differentiate methylation from hydroxymethylation and analysis of limited input/single-cells, have great promise for continuing to expand epigenomic capabilities. This review provides a background on DNA modifications, the current state-of-theart for sequencing methods, bioinformatics tools for converting these large data sets into biological insights, and perspectives on future directions for the field.

show abstract

DNA N6-methyladenine is dynamically regulated in the mouse brain following environmental stress

Cited by 182 publications

References 56 publications

N-methyladenine DNA Modification in Glioblastoma

N-methyladenine DNA Modification in Glioblastoma

Brain iron loading impairs DNA methylation and alters GABAergic function in mice

Analysis of DNA modifications in aging research

Contact Info

Product

Resources

About