The Mammalian de Novo DNA Methyltransferases DNMT3A and DNMT3B Are Also DNA 5-Hydroxymethylcytosine Dehydroxymethylases

Chen, Sean Chun-Chang; Wang, Keh Yang; Shen, Che Kun James

doi:10.1074/jbc.c112.406975

Cited by 169 publications

(143 citation statements)

References 42 publications

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“…Observations made in vitro may explain this apparent paradox. Dnmt3a has been shown to function as a DNA demethylase under conditions of elevated Ca 2+ levels whereas the methyltransferase activity was reinstated after raising SAM levels (31)(32)(33). Induction of IEGs in DG neurons in vivo requires the opening of NMDA receptors, allowing a sustained rise in intracellular Ca 2+ levels (11).…”

Section: Discussionmentioning

confidence: 99%

Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus

Saunderson

Spiers

Mifsud

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

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Stressful events evoke long-term changes in behavioral responses; however, the underlying mechanisms in the brain are not well understood. Previous work has shown that epigenetic changes and immediate-early gene (IEG) induction in stress-activated dentate gyrus (DG) granule neurons play a crucial role in these behavioral responses. Here, we show that an acute stressful challenge [i.e., forced swimming (FS)] results in DNA demethylation at specific CpG (5′-cytosine-phosphateguanine-3′) sites close to the c-Fos (FBJ murine osteosarcoma viral oncogene homolog) transcriptional start site and within the gene promoter region of Egr-1 (early growth response protein 1) specifically in the DG. Administration of the (endogenous) methyl donor S-adenosyl methionine (SAM) did not affect CpG methylation and IEG gene expression at baseline. However, administration of SAM before the FS challenge resulted in an enhanced CpG methylation at the IEG loci and suppression of IEG induction specifically in the DG and an impaired behavioral immobility response 24 h later. The stressor also specifically increased the expression of the de novo DNA methyltransferase Dnmt3a [DNA (cytosine-5-)-methyltransferase 3 alpha] in this hippocampus region. Moreover, stress resulted in an increased association of Dnmt3a enzyme with the affected CpG loci within the IEG genes. No effects of SAM were observed on stress-evoked histone modifications, including H3S10p-K14ac (histone H3, phosphorylated serine 10 and acetylated lysine-14), H3K4me3 (histone H3, trimethylated lysine-4), H3K9me3 (histone H3, trimethylated lysine-9), and H3K27me3 (histone H3, trimethylated lysine-27). We conclude that the DNA methylation status of IEGs plays a crucial role in FS-induced IEG induction in DG granule neurons and associated behavioral responses. In addition, the concentration of available methyl donor, possibly in conjunction with Dnmt3a, is critical for the responsiveness of dentate neurons to environmental stimuli in terms of gene expression and behavior.stress | behavior | DNA methylation | immediate-early gene | hippocampus A daptation to stressful challenges is crucial for maintaining health and well-being. These events induce physiological and behavioral responses that enable the individual to cope with the challenge. In the brain, molecular mechanisms are initiated that facilitate learning of adaptive behavioral responses and the consolidation of memories of the event. Inappropriate responses to stress have been linked with psychiatric disorders, such as major depression and anxiety (1-3).Glucocorticoid hormones, secreted in response to a stressful challenge, in conjunction with activated intracellular signaling pathways in neurons of the hippocampus, play a key role in consolidating behavioral responses to stress (4, 5). The hippocampal extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) pathway, activated through N-methyl D-aspartate receptors (NMDA-Rs) and other membrane receptors, is involved in behavioral responses seen in Mo...

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Section: Discussionmentioning

confidence: 99%

Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus

Saunderson

Spiers

Mifsud

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

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“…28,29 Interestingly, Chen et al found that the de novo methyltransferases DNMT3a and DNMT3b act as both DNA methyltransferases and DNA dehydroxymethylases, depending upon the redox environment: treatment with dithiothreitol (DTT) or hydrogen peroxide (H 2 O 2 ) inhibited and enhanced the dehydroxymethylation activities of the enzymes, respectively. 30 Chen et al speculated that the dual methylation and dehydroxymethylation activities of the DNMT3 enzymes might explain the paradoxical observation that DMNT3 expression is upregulated and gene-specific DNA methylation is increased in cancer cells, yet global DNA methylation is decreased. 30 Histone deacetylase (HDAC) inhibition has been shown experimentally to induce DNA hypomethylation, 31 and it has been hypothesized that HDAC activities might also be influenced directly by cellular redox.…”

Section: Discussionmentioning

confidence: 99%

“…30 Chen et al speculated that the dual methylation and dehydroxymethylation activities of the DNMT3 enzymes might explain the paradoxical observation that DMNT3 expression is upregulated and gene-specific DNA methylation is increased in cancer cells, yet global DNA methylation is decreased. 30 Histone deacetylase (HDAC) inhibition has been shown experimentally to induce DNA hypomethylation, 31 and it has been hypothesized that HDAC activities might also be influenced directly by cellular redox. 32 In human neuroblastoma cells, exposure to H 2 O 2 induces global DNA hypomethylation, along with downregulation of HDAC3, DNMT1 and DNMT3a expression.…”

Section: Discussionmentioning

confidence: 99%

Blood glutathione redox status and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults

et al. 2013

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“…DNMT3A and DNMT3B are de novo DNA methyltransferases, and together with the maintenance methyltransferase DNMT1 are necessary for DNA methylation essential for embryonic development (Li et al, 1992, Okano et al, 1999. Other functions for these enzymes have been reported recently, but will not be discussed here (Chen et al, 2012). In germ cells, DNMT3L is expressed in testes at the stage of de novo methylation, and interacts with DNMT3A and B (Bourc'his and Bestor, 2004).…”

Section: Dna Methylation Development and Cancermentioning

confidence: 99%

Role of epigenetics in the etiology of germ cell cancer

Zwan¹,

Stoop²,

Rossello³

et al. 2013

Int. J. Dev. Biol.

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Embryonic development is strictly controlled by functionality of genes in which the existing networks can act both on transcription and translation regulation. Germ cell cancers (GCC) are unique because of a number of characteristics. In spite of their clinical presentation, i.e., predominantly after puberty, they arise from primordial germ cells/gonocytes that have failed appropriate maturation to either pre-spermatogonia or oogonia. GCC mimic embryonal development to a certain extent, including capacity for totipotency. This knowledge has allowed the identification of informative diagnostic markers, including OCT3/4 (POU5F1), SOX2 and SOX17. An additional marker is the overall demethylated status of the genome. Genetic mutations in GCC are rare, which is exceptional for solid cancers. Our hypothesis is that a disturbed epigenetic regulation (through combined interaction of genetic or environmental parameters; referred to as genvironment) affect embryonic germ cell development, resulting in delayed or blocked maturation, and potentially progression to GCC. In this respect, studies of patients with Disorders of Sex Development (DSD) have increased our knowledge significantly. Genvironmental influences can lead to retention of existence of embryonic germ cells, the first step in the pathogenesis of GCC, resulting into the precursor lesions gonadoblastoma or carcinoma in situ. Identification of epigenetic alterations could lead to better understanding these processes and development of specific markers for early detection, eventually leading to development of targeted treatment. This review describes an interactive model related to the role of epigenetics in GCC pathogenesis, focusing on DNA methylation, histone modifications, epigenetic memory and inheritance, as well as environmental factors.

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The Mammalian de Novo DNA Methyltransferases DNMT3A and DNMT3B Are Also DNA 5-Hydroxymethylcytosine Dehydroxymethylases

Cited by 169 publications

References 42 publications

Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus

Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus

Blood glutathione redox status and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults

Role of epigenetics in the etiology of germ cell cancer

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