N6-Methyladenine DNA Modification in the Human Genome

Xiao, Chuan-Le; Zhu, Shuguang; He, Minghui; Chen, De; Zhang, Qian; Chen, Ying; Yu, Guoliang; Liu, Jinbao; Xie, Shuang; Luo, Feng; Liang, Zhe; Wang, Depeng; Bo, Xiaochen; Gu, Xiaofeng; Wang, Kai; Yan, Guang-Rong

doi:10.1016/j.molcel.2018.06.015

Cited by 434 publications

(409 citation statements)

References 50 publications

(105 reference statements)

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“…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: 91%

“…N 6 -mA levels were elevated in other central nervous system cancers, including diffuse intrinsic pontine glioma (DIPG), meningioma, and medulloblastoma, compared to normal human astrocytes (Figure S1D). Of note, a recent study reported high levels of N 6 -mA in normal human adult tissues (at several hundred PPM), with downregulation in gastric and stomach cancers (Xiao et al, 2018). However, our current study, together with other previous studies (Zhu et al, 2018) did not find high levels of N 6 -mA in normal adult tissues or mammalian cells.…”

Section: Resultsmentioning

confidence: 99%

“…N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) was recently suggested as a DNA N 6 -mA methyltransferase in human cells (Xiao et al, 2018). In light of these findings, we interrogated the function of N6AMT1 in patient-derived GSCs.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to the canonical 5mC, other DNA methylation events, including N(6)-methyladenine ( N 6 -mA), have been identified in bacteria (Vanyushin et al, 1968) and a limited number of eukaryotes, such as mosquitoes, plants, C. elegans and Drosophila (Fu et al, 2015; Greer et al, 2015; Rogers and Rogers, 1995; Yao et al, 2017; Zhang et al, 2015). We recently demonstrated that N 6 -mA DNA methylation occurs in mammals, where it acts mainly as a repressive mark to silence transcription of LINE transposons in mouse embryonic stem cells (ESCs) (Wu et al, 2016) and this modification has also been reported in human tissue (Xiao et al, 2018; Zhu et al, 2018). However, the roles of N 6 -mA in human cancer and in genome biology are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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N-methyladenine DNA Modification in Glioblastoma

Xie

Gimple

et al. 2018

Cell

263

266

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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.

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Section: Discussionmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

N-methyladenine DNA Modification in Glioblastoma

Xie

Gimple

et al. 2018

Cell

263

266

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“…DOI 10.1002/em one study, substrate turnover by TDG was reportedly enhanced by the NEIL enzymes (Schomacher et al, 2016). 2B; Xiao et al, 2018;Kweon et al, 2019). 5hmC may also be deaminated to 5hmU, which can be recognized by TDG, single-strand selective monofunctional U-DNA glycosylase (SMUG1), MBD4, or the NEIL1 DNA glycosylase and repaired via BER (reviewed in Bayraktar and Kreutz, 2018).…”

Section: The Enigma Of Mtdna Methylationmentioning

confidence: 99%

Mitochondrial DNA: Epigenetics and environment

Sharma

Pasala

Prakash

2019

Environ and Mol Mutagen

127

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Maintenance of the mitochondrial genome is essential for proper cellular function. For this purpose, mitochondrial DNA (mtDNA) needs to be faithfully replicated, transcribed, translated, and repaired in the face of constant onslaught from endogenous and environmental agents. Although only 13 polypeptides are encoded within mtDNA, the mitochondrial proteome comprises over 1500 proteins that are encoded by nuclear genes and translocated to the mitochondria for the purpose of maintaining mitochondrial function. Regulation of mtDNA and mitochondrial proteins by epigenetic changes and post‐translational modifications facilitate crosstalk between the nucleus and the mitochondria and ultimately lead to the maintenance of cellular health and homeostasis. DNA methyl transferases have been identified in the mitochondria implicating that methylation occurs within this organelle; however, the extent to which mtDNA is methylated has been debated for many years. Mechanisms of demethylation within this organelle have also been postulated, but the exact mechanisms and their outcomes is still an active area of research. Mitochondrial dysfunction in the form of altered gene expression and ATP production, resulting from epigenetic changes, can lead to various conditions including aging‐related neurodegenerative disorders, altered metabolism, changes in circadian rhythm, and cancer. Here, we provide an overview of the epigenetic regulation of mtDNA via methylation, long and short noncoding RNAs, and post‐translational modifications of nucleoid proteins (as mitochondria lack histones). We also highlight the influence of xenobiotics such as airborne environmental pollutants, contamination from heavy metals, and therapeutic drugs on mtDNA methylation. Environ. Mol. Mutagen., 60:668–682, 2019. © 2019 Wiley Periodicals, Inc.

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Small Protein Hidden in lncRNA LOC90024 Promotes “Cancerous” RNA Splicing and Tumorigenesis

Meng

Chen

et al. 2020

Advanced Science

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Conventional therapies for late‐stage colorectal cancer (CRC) have limited effects because of chemoresistance, recurrence, and metastasis. The “hidden” proteins/peptides encoded by long noncoding RNAs (lncRNAs) may be a novel resource bank for therapeutic options for patients with cancer. Here, lncRNA LOC90024 is discovered to encode a small 130‐amino acid protein that interacts with several splicing regulators, such as serine‐ and arginine‐rich splicing factor 3 (SRSF3), to regulate mRNA splicing, and the protein thus is named “Splicing Regulatory Small Protein” (SRSP). SRSP, but not LOC90024 lncRNA itself, promotes CRC tumorigenesis and progression, while silencing of SRSP suppresses CRC tumorigenesis. Mechanistically, SRSP increases the binding of SRSF3 to exon 3 of transcription factor Sp4, resulting in the inclusion of Sp4 exon 3 to induce the formation of the “cancerous” long Sp4 isoform (L‐Sp4 protein) and inhibit the formation of the “noncancerous” short Sp4 isoform (S‐Sp4 peptide), which lacks the transactivation domain. The upregulated SRSP level is positively associated with malignant phenotypes and poor prognosis in patients with CRC. Collectively, the findings uncover that a lncRNA‐encoded small protein SRSP induces “cancerous” Sp4 splicing variant formation and may be a potential prognostic biomarker and therapeutic target for patients with CRC.

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N6-Methyladenine DNA Modification in the Human Genome

Cited by 434 publications

References 50 publications

N-methyladenine DNA Modification in Glioblastoma

N-methyladenine DNA Modification in Glioblastoma

Mitochondrial DNA: Epigenetics and environment

Small Protein Hidden in lncRNA LOC90024 Promotes “Cancerous” RNA Splicing and Tumorigenesis

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