5-hmC–mediated epigenetic dynamics during postnatal neurodevelopment and aging

Szulwach, Keith E.; Li, Xuekun; Li, Yujing; Song, Chun-Xiao; Wu, Hao; Dai, Qing; Irier, Hasan A.; Upadhyay, Anup K.; Gearing, Marla; Levey, Aĺlan I.; Vasanthakumar, Aparna; Godley, Lucy A.; Chang, Qiang; Cheng, Xiaodong; He, Chuan; Jin, Peng

doi:10.1038/nn.2959

Cited by 759 publications

(836 citation statements)

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“…49 Recently, by microarray analysis, Suzlwach et al found no significant increase in Tet family gene expression during neurodevelopment although 5hmC markedly increased from the early postnatal stage to adulthood. 49 The observation hinted an additional factor required for regulating the 5hmC formation in neurons. Our work suggests that AA may partly contribute to the dynamics of DNA methylation in brain development.…”

Section: ■ Discussionmentioning

confidence: 99%

Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals

et al. 2013

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DNA hydroxymethylation and its mediated DNA demethylation are critical for multiple cellular processes, for example, nuclear reprogramming, embryonic development, and many diseases. Here, we demonstrate that a vital nutrient ascorbic acid (AA), or vitamin C (Vc), can directly enhance the catalytic activity of Tet dioxygenases for the oxidation of 5-methylcytosine (5mC). As evidenced by changes in intrinsic fluorescence and catalytic activity of Tet2 protein caused by AA and its oxidation-resistant derivatives, we further show that AA can uniquely interact with the C-terminal catalytic domain of Tet enzymes, which probably promotes their folding and/or recycling of the cofactor Fe 2+ . Other strong reducing chemicals do not have a similar effect. These results suggest that AA also acts as a cofactor of Tet enzymes. In mouse embryonic stem cells, AA significantly increases the levels of all 5mC oxidation products, particularly 5-formylcytosine and 5-carboxylcytosine (by more than an order of magnitude), leading to a global loss of 5mC (∼40%). In cells deleted of the Tet1 and Tet2 genes, AA alters neither 5mC oxidation nor the overall level of 5mC. The AA effects are however restored when Tet2 is re-expressed in the Tet-deficient cells. The enhancing effects of AA on 5mC oxidation and DNA demethylation are also observed in a mouse model deficient in AA synthesis. Our data establish a direct link among AA, Tet, and DNA methylation, thus revealing a role of AA in the regulation of DNA modifications. ■ INTRODUCTIONDNA demethylation remarkably contributes to the dynamics of the epigenetic marker 5-methylcytosine (5mC) in mammals and is critical for multiple biological processes, including animal cloning, 1 nuclear reprogramming, 2,3 development, 4−8 and highly locus-specific regulation of gene activities. 9−11 DNA demethylation can be initiated by the oxidation of 5mC and the formation of 5-hydroxymethylcytosine (5hmC), which are catalyzed by ten eleven translocation (Tet) family dioxygenases. 12−15 The formed 5hmC can be diluted by DNA replication, suggesting a passive DNA demethylation pathway. 16 Moreover, the 5hmC can be further oxidized by Tet proteins to form 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be excised by thymine DNA glycosylase (TDG) followed by the reintroduction of unmethylated cytosine through the base-excision repair (BER) pathway. 14,15 This important pathway for active DNA demethylation has been thought to be involved in a number of prominent biological processes. 5,6,10,11 Early and recent studies suggested that active and replication-independent DNA demethylation might be a rapid process. 10,11 The radically altered methylation, as observed in replication-independent demethylation of the paternal genome in zygotes, may complete within hours. 5,6,17−19 However, the observed levels of the active DNA demethylation intermediates, 5fC and 5caC in the cultured cells, were 100-fold less than the primary product 5hmC. 13−15,20−22 Biochemically, the Tet-mediated DNA dem...

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Section: ■ Discussionmentioning

confidence: 99%

Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals

et al. 2013

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“…One very recent example is represented by the studies on the role of the 5-hydroxymethylation in regulating gene expression [ 90 ]; these results shed new light on the role and the extent of hydroxymethylation have since shown the possibility that this, so far, underrepresented epigenetic modification may have a role in pathogenic processes. A second example is given by the studies about the theory, abovementioned, that epigenetic changes may occur in the early life but become manifest in elderly.…”

Section: Dna Methylation and Neurodegenerationmentioning

confidence: 99%

The ‘golden age’ of DNA methylation in neurodegenerative diseases

Fuso¹

2013

Clinical Chemistry and Laboratory Medicine

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DNA methylation reactions are regulated, in the first instance, by enzymes and the intermediates that constitute the ' so called ' one-carbon metabolism. This is a complex biochemical pathway, also known as the homocysteine cycle, regulated by the presence of B vitamins (folate, B6, B12) and choline, among other metabolites. One of the intermediates of this metabolism is S-adenosylmethionine, which represent the methyl donor in all the DNA methyltransferase reactions in eukaryotes. The one-carbon metabolism therefore produces the substrate necessary for the transferring of a methyl group on the cytosine residues of DNA; S-adenosylmethionine also regulates the activity of the enzymes that catalyze this reaction, namely the DNA methyltransferases (DNMTs). Alterations of this metabolic cycle can therefore be responsible for aberrant DNA methylation processes possibly leading to several human diseases. As a matter of fact, increasing evidences indicate that a number of human diseases with multifactorial origin may have an epigenetic basis. This is also due to the great technical advances in the field of epigenetic research. Among the human diseases associated with epigenetic factors, aging-related and neurodegenerative diseases are probably the object of most intense research. This review will present the main evidences linking seve ral human diseases to DNA methylation, with particular focus on neurodegenerative diseases, together with a short description of the state-of-the-art of methylation assays.

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“…Previous studies indicate that 5hmC is enriched in the exons of highly expressed genes in brain tissues, and in cis-regulatory elements such as active enhancers, insulatorbinding sites in ESCs [22][23][24][25][26][27][28] . Enrichment of 5hmC is also found in the promoter region of polycomb-repressed 'poised' genes in ESCs [23][24][25]27 , which disappeared in the adult brain 29 . By comparing the genomic distribution of 5hmC in mouse hippocampus and cerebellum at three different ages, we have shown that it exhibits dynamic changes during brain development and aging 29 .…”

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confidence: 96%

“…Enrichment of 5hmC is also found in the promoter region of polycomb-repressed 'poised' genes in ESCs [23][24][25]27 , which disappeared in the adult brain 29 . By comparing the genomic distribution of 5hmC in mouse hippocampus and cerebellum at three different ages, we have shown that it exhibits dynamic changes during brain development and aging 29 .…”

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confidence: 96%

Dynamics of 5-hydroxymethylcytosine during mouse spermatogenesis

et al. 2013

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Little is known about how patterns of DNA methylation change during mammalian spermatogenesis. 5hmC has been recognized as a stable intermediate of DNA demethylation with potential regulatory functions in the mammalian genome. However, its global pattern in germ cells has yet to be addressed. Here, we first conducted absolute quantification of 5hmC in eight consecutive types of mouse spermatogenic cells using liquid chromatographytandem mass spectrometry, and then mapped its distributions in various genomic regions using our chemical labeling and enrichment method coupled with deep sequencing. We found that 5hmC mapped differentially to and changed dynamically in genomic regions related to expression regulation of protein-coding genes, piRNA precursor genes and repetitive elements. Moreover, 5hmC content correlated with the levels of various transcripts quantified by RNA-seq. These results suggest that the highly ordered alterations of 5hmC in the mouse genome are potentially crucial for the differentiation of spermatogenic cells.

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5-hmC–mediated epigenetic dynamics during postnatal neurodevelopment and aging

Cited by 759 publications

References 50 publications

Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals

Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals

The ‘golden age’ of DNA methylation in neurodegenerative diseases

Dynamics of 5-hydroxymethylcytosine during mouse spermatogenesis

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