Editors' ChoiceDNA Modifications

Demethylation Needed to Forget

Sci. Signal.  24 Sep 2013:
Vol. 6, Issue 294, pp. ec227
DOI: 10.1126/scisignal.2004739

Not only are the proteins around which DNA winds modified posttranslationally, DNA itself exhibits dynamic epigenetic changes, such as those affecting cytosine. Kaas et al. and Rudenko et al. both examined the importance of DNA demethylation, promoted by the enzyme Tet1, in synaptic plasticity in the brain. Both groups developed methods to quantify the amount of 5-methylcytosine (5mC), which is the substrate of Tet1, and 5-hydroxymethylcytosine (5hmC), which is the product. Kaas et al. found that a seizure-inducing stimulation paradigm reduced the abundance of 5mC 3 hours after seizure in the hippocampus and that both 5mC and 5hmC were reduced 24 hours later, which indicated that synaptic activity alters this form of DNA modification. The abundance of Tet1 transcript, but not that of Tet2 or Tet3, was reduced 3 hours after stimulation of neurons in culture or in the hippocampi of mice exposed to the seizure-inducing paradigm or a fear-conditioning paradigm. Overexpression of the catalytic domain of Tet1 in the hippocampus increased the proportion of 5hmC and of unmodified cytosines. Overexpression of the active catalytic domain or an inactive mutant form of Tet1 increased the abundance of transcripts associated with synaptic plasticity in the hippocampus. Animals injected with either of the Tet1 catalytic domain–expressing viruses exhibited impaired long-term memory. Rudenko et al. reported that, in Tet1 knockout (Tet1 KO) mice, the global abundance of 5hmC was decreased in the hippocampus and cortex compared with that in wild-type controls. In behavior and memory tests, the mice exhibited normal memory acquisition but impaired memory extinction. Electrophysiological analysis of hippocampal slices of Tet1 KO mice revealed enhanced long-term depression but not differences in basal synaptic activity or long-term potentiation relative to wild-type. Examination of Npas4 and c-Fos, two proteins implicated in synaptic plasticity, revealed that the transcript and protein abundances were reduced in the Tet1 KO mice. Furthermore, the Npas4 promoter region exhibited an increased proportion of methylated cytosines in the cortex and hippocampus of Tet1 KO mice compared with that of wild-type mice after fear extinction training. Although fear-conditioning training stimulated the expression of both Npas4 and c-Fos in both mice, extinction training only stimulated the expression of these genes in the wild-type mice. Thus, there appear to be specific roles for dynamic changes in DNA cytosine methylation in specific forms of synaptic plasticity. However, open questions remain regarding how both the catalytically active and catalytically inactive forms of Tet1 both compromised memory and altered transcription of the same genes associated with synaptic plasticity and regarding how the same type of activity-stimulating paradigm can reduce the abundance of the Tet1 transcript, yet promote the demethylation of cytosines.

G. A. Kaas, C. Zhong, D. E. Eason, D. L. Ross, R. V. Vachhani, G.-l. Ming, J. R. King, H. Song, J. D. Sweatt, TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron 79, 1086–1093 (2013).[Online Journal]

A. Rudenko, M. M. Dawlaty, J. Seo, A. W. Cheng, J. Meng, T. Le, K. F. Faull, R. Jaenisch, L.-H. Tsai, Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron 79, 1109–1122 (2013).[Online Journal]

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