Changes of DNA methylation level during pre-and postnatal periods in mice

Tawa, Riichi; Ono, Tetsuya; Kurishita, Akihiro; Okada, S.; Hirose, Shingo

doi:10.1111/j.1432-0436.1990.tb00455.x

Cited by 62 publications

(39 citation statements)

References 53 publications

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“…Effects of DNMT inhibition on miniature postsynaptic currents and synapse number To examine whether alterations in DNA methylation influence synaptic transmission, hippocampal neurons were cultured from newborn C57BL/6 mice, matured (13-21 DIV) (Mozhayeva et al, 2002), and treated for 24 h with two different DNMT inhibitors, the methylcytosine analogs 5azaC or Zeb (Tawa et al, 1990). Wholecell voltage-clamp recordings were performed on cultured hippocampal neurons immediately after 24 h chronic treatments.…”

Section: Resultsmentioning

confidence: 99%

Activity-Dependent Suppression of Miniature Neurotransmission through the Regulation of DNA Methylation

Nelson¹,

Kavalali²,

Monteggia³

2008

J. Neurosci.

236

192

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DNA methylation is an epigenetic mechanism that plays a critical role in the repression of gene expression. Here, we show that DNA methyltransferase (DNMT) inhibition in hippocampal neurons results in activity-dependent demethylation of genomic DNA and a parallel decrease in the frequency of miniature EPSCs (mEPSCs), which in turn impacts neuronal excitability and network activity. Treatment with DNMT inhibitors reveals an activity-driven demethylation of brain-derived neurotrophic factor promoter I, which is mediated by synaptic activation of NMDA receptors, because it is susceptible to AP-5, a blocker of NMDA receptors. The specific effect of DNMT inhibition on spontaneous excitatory neurotransmission requires gene transcription and is occluded in the absence of the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2). Interestingly, enhancing excitatory activity, in the absence of DNMT inhibitors, also produces similar decreases in DNA methylation and mEPSC frequency, suggesting a role for DNA methylation in the control of homeostatic synaptic plasticity. Furthermore, adding excess substrate for DNA methylation (S-adenosyl-L-methionine) rescues the suppression of mEPSCs by DNMT inhibitors in wild-type neurons, as well as the defect seen in MeCP2-deficient neurons. These results uncover a means by which NMDA receptor-mediated synaptic activity drives DNA demethylation within mature neurons and suppresses basal synaptic function.

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Section: Resultsmentioning

confidence: 99%

Activity-Dependent Suppression of Miniature Neurotransmission through the Regulation of DNA Methylation

Nelson¹,

Kavalali²,

Monteggia³

2008

J. Neurosci.

236

192

View full text Add to dashboard Cite

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“…Interestingly, the mammalian brain expresses high levels of Dnmt1 both during development and in adulthood (Goto et al, 1994;Brooks et al, 1996;Trasler et al, 1996;Inano et al, 2000). The level of DNA methylation is higher in adult brain than in other tissues (Wilson et al, 1987;Tawa et al, 1990;Ono et al, 1993). Perinatally, DNA methylation levels in the brain undergo a dynamic change (Tawa et al, 1990), suggesting a role for DNA methylation in the differentiation process of the brain.…”

mentioning

confidence: 99%

“…The level of DNA methylation is higher in adult brain than in other tissues (Wilson et al, 1987;Tawa et al, 1990;Ono et al, 1993). Perinatally, DNA methylation levels in the brain undergo a dynamic change (Tawa et al, 1990), suggesting a role for DNA methylation in the differentiation process of the brain. Further evidence comes from a study of neuronal differentiation in PC12 cells that showed that treatment with a demethylating agent 5-azacytidine blocks neurite outgrowth and upregulates the expression of Id family transcription factors Kilpatrick, 1996, 1997).…”

mentioning

confidence: 99%

DNA Hypomethylation Perturbs the Function and Survival of CNS Neurons in Postnatal Animals

et al. 2001

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DNA methyltransferase I (Dnmt1), the maintenance enzyme for DNA cytosine methylation, is expressed at high levels in the CNS during embryogenesis and after birth. Because embryos deficient for Dnmt1 die at gastrulation, the role of Dnmt1 in the development and function of the nervous system could not be studied by using this mutation. We therefore used the cre/loxP system to produce conditional mutants that lack Dnmt1 in neuroblasts of embryonic day 12 embryos or in postmitotic neurons of the postnatal animal. Conditional deletion of the Dnmt1 gene resulted in rapid depletion of Dnmt1 proteins, indicating that the enzyme in postmitotic neurons turns over quickly. Dnmt1 deficiency in postmitotic neurons neither affected levels of global DNA methylation nor influenced cell survival during postnatal life. In contrast, Dnmt1 deficiency in mitotic CNS precursor cells resulted in DNA hypomethylation in daughter cells. Whereas mutant embryos carrying 95% hypomethylated cells in the brain died immediately after birth because of respiratory distress, mosaic animals with 30% hypomethylated CNS cells were viable into adulthood. However, these mutant cells were eliminated quickly from the brain within 3 weeks of postnatal life. Thus, hypomethylated CNS neurons were impaired functionally and were selected against at postnatal stages.

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“…DNMTs are abundantly expressed in the brain, spinal cord, and DRG [40,[86][87][88]. Coincidently, global DNA methylation levels are higher in the adult brain than in other tissues [89][90][91]. Cytosine methylation seems to be dynamically regulated in the adult CNS, thus it might be directly involved in gene expression regulation upon physiological changes.…”

Section: Dna Methylation In Neuronal Plasticity and Axonal Injurymentioning

confidence: 99%

Epigenetic Regulation of Axon Outgrowth and Regeneration in CNS Injury: The First Steps Forward

2013

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Inadequate axonal sprouting and lack of regeneration limit functional recovery following neurologic injury, such as stroke, brain, and traumatic spinal cord injury. Recently, the enhancement of the neuronal regenerative program has led to promising improvements in axonal sprouting and regeneration in animal models of axonal injury. However, precise knowledge of the essential molecular determinants of this regenerative program remains elusive, thus limiting the choice of fully effective therapeutic strategies. Given that molecular regulation of axonal outgrowth and regeneration requires carefully orchestrated waves of gene expression, both temporally and spatially, epigenetic changes may be an ideal regulatory mechanism to address this unique need. While recent evidence suggests that epigenetic modifications could contribute to the regulation of axonal outgrowth and regeneration following axonal injury in models of stroke, and spinal cord and optic nerve injury, a number of unanswered questions remain. Such questions require systematic investigation of the epigenetic landscape between regenerative and non-regenerative conditions for the potential translation of this knowledge into regenerative strategies in human spinal and brain injury, as well as stroke.

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Changes of DNA methylation level during pre-and postnatal periods in mice

Cited by 62 publications

References 53 publications

Activity-Dependent Suppression of Miniature Neurotransmission through the Regulation of DNA Methylation

Activity-Dependent Suppression of Miniature Neurotransmission through the Regulation of DNA Methylation

DNA Hypomethylation Perturbs the Function and Survival of CNS Neurons in Postnatal Animals

Epigenetic Regulation of Axon Outgrowth and Regeneration in CNS Injury: The First Steps Forward

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