Active N6-Methyladenine Demethylation by DMAD Regulates Gene Expression by Coordinating with Polycomb Protein in Neurons

Yao, Bing; Li, Yujing; Wang, Zhiqin; Chen, Li; Poidevin, Mickaël; Zhang, Can; Lin, Li; Wang, Feng; Bao, Han; Jiao, Bin; Lim, Jung Hwa; Cheng, Ying; Huang, Luoxiu; Phillips, Brittany L.; Xu, Tianlei; Duan, Ranhui; Moberg, Kenneth H.; Wu, Hao; Jin, Peng

doi:10.1016/j.molcel.2018.07.005

Cited by 69 publications

(96 citation statements)

References 42 publications

(63 reference statements)

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“…Methylation of adenine, i.e., 6-mA, in GATC context has been reported for the survival of several bacteria, as DNA adenine methyl transferase (DAMT, the writer) creates specific methylation marks (Figure 3) that are important for DNA replication, mismatch repair, segregation, and regulation of gene expression (Ratel et al, 2006). 6-mA is known to play an important regulatory role in RNAs, and recent studies suggest the presence of 6-mA in eukaryotic genomes (Kigar et al, 2017; Yao et al, 2017, 2018). Moreover, oxidation of the methyl group of 6-mA by AlkB family of dioxygenases (e.g., 6-mA demethylases) results in the formation of 6-hmA and 6-fA, which can restore the original base (Figure 3) by releasing formaldehyde (Fu et al, 2013).…”

Section: Non-cytosine Methylation Of Dna: N6-methyladeninementioning

confidence: 99%

“…Their finding indicates that cytosine and adenine (de)methylation occur in a coordinated, dynamic and sequence context-specific manner. Recently, Yao et al (2018) reported epigenetic regulation of a group of genes involved in neurodevelopment and neuronal functions in D. melanogaster . Accumulation of 6-mA due to deactivated DMAD coordinates with Polycomb proteins and contributes to transcriptional repression of the genes.…”

Section: Non-cytosine Methylation Of Dna: N6-methyladeninementioning

confidence: 99%

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Epigenetics of Modified DNA Bases: 5-Methylcytosine and Beyond

2018

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Modification of DNA bases plays vital roles in the epigenetic control of gene expression in both animals and plants. Though much attention is given to the conventional epigenetic signature 5-methylcytosine (5-mC), the field of epigenetics is attracting increased scientific interest through the discovery of additional modifications of DNA bases and their roles in controlling gene expression. Theoretically, each of the DNA bases can be modified; however, modifications of cytosine and adenine only are known so far. This review focuses on the recent findings of the well-studied cytosine modifications and yet poorly characterized adenine modification which serve as an additional layer of epigenetic regulation in animals and discuss their potential roles in plants. Cytosine modification at symmetric (CG, CHG) and asymmetric (CHH) contexts is a key epigenetic feature. In addition to the ROS1 family mediated demethylation, Ten-Eleven Translocation family proteins-mediated hydroxylation of 5-mC to 5-hydroxymethylcytosine as additional active demethylation pathway are also discussed. The epigenetic marks are known to be associated with the regulation of several cellular and developmental processes, pluripotency of stem cells, neuron cell development, and tumor development in animals. Therefore, the most recently discovered N6-methyladenine, an additional epigenetic mark with regulatory potential, is also described. Interestingly, these newly discovered modifications are also found in the genomes which lack canonical 5-mC, signifying their independent epigenetic functions. These modified DNA bases are considered to be important players in epigenomics. The potential for combinatorial interaction among the known modified DNA bases suggests that epigenetic codon is likely to be substantially more complicated than it is thought today.

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Section: Non-cytosine Methylation Of Dna: N6-methyladeninementioning

confidence: 99%

Section: Non-cytosine Methylation Of Dna: N6-methyladeninementioning

confidence: 99%

Epigenetics of Modified DNA Bases: 5-Methylcytosine and Beyond

2018

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“…This effect can be overcome by ATP-dependent chromatin remodelers in vitro. We expect the biochemical impact of 6mA to be directly pertinent across a wide range of eukaryotic genomes, including vertebrates, C. elegans, Drosophila and fungi, where this 24 epigenetic modification has recently been documented Koziol et al, 2015;Liang et al, 2018;Liu et al, 2016;Mondo et al, 2017;Wu et al, 2016;Xiao et al, 2018;Yao et al, 2018;Zhang et al, 2015). Our experiments do not reveal exactly how 6mA disfavors nucleosome occupancy.…”

Section: Discussionmentioning

confidence: 67%

“…6mA exists at low levels in Arabidopsis thaliana (0.006%-0.138% 6mA / dA), rice (0.2%), C. elegans (0.01-0.4%), Drosophila (0.001-0.07%), Xenopus laevis (0.00009%), mouse ES cells (0.0006 -0.007%), human cells Koziol et al, 2015;Liang et al, 2018;Wu et al, 2016;Xiao et al, 2018;Zhang et al, 2015;Zhou et al, 2018) and the mouse brain (Yao et al, 2017), although it accumulates in abundance (0.1-0.2%) during vertebrate embryogenesis . Disruption of DMAD, a 6mA demethylase, in the Drosophila brain leads to the accumulation of 6mA and Polycomb-mediated silencing (Yao et al, 2018). The existence of 6mA in mammals remains a subject of debate.…”

Section: Introductionmentioning

confidence: 99%

Reconstitution of eukaryotic chromosomes and manipulation of DNA N6-methyladenine alters chromatin and gene expression

et al. 2018

Preprint

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DNA N6-adenine methylation (6mA) has recently been reported in diverse eukaryotes, spanning unicellular organisms to metazoans. Yet the functional significance of 6mA remains elusive due to its low abundance, difficulty of manipulation within native DNA, and lack of understanding of eukaryotic 6mA writers. Here, we report a novel DNA 6mA methyltransferase in ciliates, termed MTA1. The enzyme contains an MT-A70 domain but is phylogenetically distinct from all known RNA and DNA methyltransferases.Disruption of MTA1 in vivo leads to the genome-wide loss of 6mA in asexually growing cells and abolishment of the consensus ApT dimethylated motif. Genes exhibit subtle changes in chromatin organization or RNA expression upon loss of 6mA, depending on their starting methylation level. Mutants fail to complete the sexual cycle, which normally coincides with a peak of MTA1 expression. Thus, MTA1 functions in a developmental stage-specific manner. We determine the impact of 6mA on chromatin organization in vitro by reconstructing complete, full-length ciliate chromosomes harboring 6mA in native or ectopic positions. Using these synthetic chromosomes, we show that 6mA directly disfavors nucleosomes in vitro in a local, quantitative manner, independent of DNA sequence. Furthermore, the chromatin remodeler ACF can overcome this effect.Our study identifies a novel MT-A70 protein necessary for eukaryotic 6mA methylation and defines the impact of 6mA on chromatin organization using epigenetically defined synthetic chromosomes.3

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“…N6-methyladenine (6mA) and 5-methylcytosine (5mC) are the two most prevalent and well-studied base methylations. 5mC usually plays a role in embryonic development [3], atherosclerosis [4], aging and diseases [5]; and 6mA is important in transcriptional regulation [6], cancer development [7] and neurodevelopment [8].…”

Section: Introductionmentioning

confidence: 99%

DeepSignal: detecting DNA methylation state from Nanopore sequencing reads using deep-learning

Huang

Luo

et al. 2018

Preprint

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Abstract.The Oxford Nanopore sequencing enables to directly detect methylation sites in DNA from reads without extra laboratory techniques. In this study, we develop DeepSignal, a deep learning method to detect DNA methylated sites from Nanopore sequencing reads. DeepSignal construct features from both raw electrical signals and signal sequences in Nanopore reads. Testing on Nanopore reads of pUC19, E. coli and human, we show that DeepSignal can achieve both higher read level and genome level accuracy on detecting 6mA and 5mC methylation comparing to previous HMM based methods. Moreover, DeepSignal achieves similar performance cross different methylation bases and different methylation motifs. Furthermore, DeepSignal can detect 5mC and 6mA methylation states of genome sites with above 90% genome level accuracy under just 5X coverage using controlled methylation data.

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Active N6-Methyladenine Demethylation by DMAD Regulates Gene Expression by Coordinating with Polycomb Protein in Neurons

Cited by 69 publications

References 42 publications

Epigenetics of Modified DNA Bases: 5-Methylcytosine and Beyond

Epigenetics of Modified DNA Bases: 5-Methylcytosine and Beyond

Reconstitution of eukaryotic chromosomes and manipulation of DNA N6-methyladenine alters chromatin and gene expression

DeepSignal: detecting DNA methylation state from Nanopore sequencing reads using deep-learning

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