Dnmt1 and Dnmt3a are required for the maintenance of DNA methylation and synaptic function in adult forebrain neurons

By Jian Feng, Yu Zhou, S. Campbell, Thuc M. Le, E. Li, J. Sweatt, Alcino J. Silva, G. Fan. Nature Neuroscience, 2010

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Dnmt1 and Dnmt3a are important DNA methyltransferases that are expressed in postmitotic neurons, but their function in the CNS is unclear. We generated conditional mutant mice that lack Dnmt1, Dnmt3a or both exclusively in forebrain excitatory neurons and found that only double knockout (DKO) mice showed abnormal long-term plasticity in the hippocampal CA1 region together with deficits in learning and memory. Although we found no neuronal loss, hippocampal neurons in DKO mice were smaller than in the wild type; furthermore, DKO neurons showed deregulated expression of genes, including the class I MHC genes and Stat1, that are known to contribute to synaptic plasticity. In addition, we observed a significant decrease in DNA methylation in DKO neurons. We conclude that Dnmt1 and Dnmt3a are required for synaptic plasticity, learning and memory through their overlapping roles in maintaining DNA methylation and modulating neuronal gene expression in adult CNS neurons.

Subfields: Developmental and Educational Psychology, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8a985a45eba926c95ee0bc0ac9cc9ceb1d829430

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Citations in the corpus

DNA Methylation and Its Basic Function (2013, methodology): “Neither knockout of Dnmt1 nor of Dnmt3a in forebrain postmitotic neurons leads to any observable change in DNA methylation, gene expression, synaptic plasticity, or behavior (Feng et al, 2010).”
Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain (2011, neutral): “During early development, the mammalian DNA methylome is dramatically reprogrammed at two stages (Feng et al., 2010b; Gehring et al., 2009).”
Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. (2011, background): “…Tet3-mediated 5mC oxidation in zygotic DNA demethylation While DNA methylation patterns are relatively stable in somatic cells, rapid erasure of global DNA methylation patterns has been observed in developing PGCs as well as zygotes (Sasaki and Matsui 2008; S Feng et al. 2010; Wu and Zhang 2010).”
Tissue Distribution of 5-Hydroxymethylcytosine and Search for Active Demethylation Intermediates (2010, methodology): “In order to test the idea that hmC is an intermediate of such an oxidative demethylation pathway and to shine light on the distribution of hmC in mammalian tissues we applied an isotope based HPLC-MS method to quantify hmC and to detect the presence of fC, caC, and hmU in various tissues. Mass spect”
Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, positive): “…of DNMTs in the nervous system results in neurodevelopmental deficits and impaired neuronal functions (Fan et al., 2001; Fan et al., 2005; Feng et al., 2010a; LaPlant et al., 2010; Nguyen et al., 2007; Wu et al., 2010), suggesting that precise control of DNA methylation pattern is…”
Large-scale gene function analysis with PANTHER Classification System (2013, background): “…successfully analyzed data from gene expression 9,10 , proteomics 11,12 and genome-wide association study (GWAS) experiments 13,14 in diverse areas of research, such as cancer research 10,11 , neurological disorder studies 15,16 , studies of autoimmune diseases 9 and cardiac disease studies 14,17 .”